Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Beyond immune checkpoint blockade: emerging immunological strategies

Abstract

The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the field. The next chapter of immunotherapy should examine the immuno-oncology therapeutic failures, and consider the complexity of immune cell–cancer cell interactions to better design more effective anticancer drugs. Herein, we briefly review the history of immunotherapy and checkpoint blockade, highlighting important clinical failures. We discuss the critical aspects — beyond T cell co-receptors — of immune processes within the tumour microenvironment (TME) that may serve as avenues along which new therapeutic strategies in immuno-oncology can be forged. Emerging insights into tumour biology suggest that successful future therapeutics will focus on two key factors: rescuing T cell homing and dysfunction in the TME, and reappropriating mononuclear phagocyte function for TME inflammatory remodelling. New drugs will need to consider the complex cell networks that exist within tumours and among cancer types.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Therapeutic options to increase the effectiveness of antitumour T cell responses.
Fig. 2: Therapeutic options to target tumorigenic processes within the TME.

References

  1. 1.

    Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Hargadon, K. M., Johnson, C. E. & Williams, C. J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol. 62, 29–39 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Tang, J., Pearce, L., O’Donnell-Tormey, J. & Hubbard-Lucey, V. M. Trends in the global immuno-oncology landscape. Nat. Rev. Drug Discov. 17, 783–784 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    CRI Anna-Maria Kellen Clinical Accelerator Team. PD-1/PD-L1 landscape. Cancer Research Institute https://www.cancerresearch.org/scientists/immuno-oncology-landscape/pd-1-pd-l1-landscape#landscape (2019).

  8. 8.

    Keenan, T. E., Burke, K. P. & Van Allen, E. M. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 25, 389–402 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Daud, A. I. et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J. Clin. Invest. 126, 3447–3452 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Krieg, C. et al. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat. Med. 24, 144–153 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Fehlings, M. et al. Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8+ T cells. Nat. Commun. 8, 562 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Charoentong, P. et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 18, 248–262 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Li, J. et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49, 178–193 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424–441 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Jerby-Arnon, L. et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Mandal, R. et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science 364, 485–491 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Cooper, Z. A., Frederick, D. T., Ahmed, Z. & Wargo, J. A. Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma. Oncoimmunology 2, e24320 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Ascierto, P. A. et al. KEYNOTE-022 part 3: phase II randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma. Ann. Oncol. 29, viii442 (2018).

    Article  Google Scholar 

  26. 26.

    Ascierto, P. A. et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat. Med. 25, 941–946 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Reddy, S. M., Reuben, A. & Wargo, J. A. Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy. Curr. Oncol. Rep. 18, 42 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Coelho, M. A. et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity 47, 1083–1099.e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    George, S. et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46, 197–204 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Shaked, Y. The pro-tumorigenic host response to cancer therapies. Nat. Rev. Cancer 19, 667–685 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Lauss, M. et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat. Commun. 8, 1738 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Fellner, C. Ipilimumab (Yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. P. T. 37, 503–530 (2012).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Ribas, A. et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31, 616–622 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Rizvi, N. A. et al. Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. Ann. Oncol. 28 (Suppl. 10), x39–x43 (2018).

    Google Scholar 

  35. 35.

    Maio, M. et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 18, 1261–1273 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Furness, A. J., Vargas, F. A., Peggs, K. S. & Quezada, S. A. Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies. Trends Immunol. 35, 290–298 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Kelley, R. K. et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J. Clin. Oncol. 38, 4508 (2020).

    Article  Google Scholar 

  39. 39.

    Mahoney, K. M., Freeman, G. J. & McDermott, D. F. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin. Ther. 37, 764–782 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Burstein, H. J. et al. Clinical cancer advances 2017: annual report on progress against cancer from the American Society of Clinical Oncology. J. Clin. Oncol. 35, 1341–1367 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Drugs.com. Yervoy FDA approval history. Drugs.com https://www.drugs.com/history/yervoy.html (2020).

  42. 42.

    Hodi, F. S. et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 19, 1480–1492 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Schmidt, C. The benefits of immunotherapy combinations. Nature 552, S67–S69 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Emens, L. et al. Abstract PD3-01: Results from KATE2, a randomized phase 2 study of atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC). Cancer Res. 79 (Suppl. 4), PD3-01 (2019).

    Google Scholar 

  46. 46.

    Olson, B., Li, Y., Lin, Y., Liu, E. T. & Patnaik, A. Mouse models for cancer immunotherapy research. Cancer Discov. 8, 1358–1365 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Buqué, A. & Galluzzi, L. Modeling tumor immunology and immunotherapy in mice. Trends Cancer 4, 599–601 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  48. 48.

    Zia, M. I., Siu, L. L., Pond, G. R. & Chen, E. X. Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. J. Clin. Oncol. 23, 6982–6991 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Bendell, J. C. et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J. Clin. Oncol. 34, 3502 (2016).

    Article  Google Scholar 

  50. 50.

    Hellmann, M. D. et al. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann. Oncol. 30, 1134–1142 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Eng, C. et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 20, 849–861 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Mushti, S. L., Mulkey, F. & Sridhara, R. Evaluation of overall response rate and progression-free survival as potential surrogate endpoints for overall survival in immunotherapy trials. Clin. Cancer Res. 24, 2268–2275 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Seruga, B., Ocana, A., Amir, E. & Tannock, I. F. Failures in phase III: causes and consequences. Clin. Cancer Res. 21, 4552–4560 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Davis, A. A. & Patel, V. G. The role of PD-L1 expression as a predictive biomarker: an analysis of all US food and drug administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer 7, 278 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Marabelle, A. et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J. Clin. Oncol. 38, 1–10 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Marabelle, A. et al. 1192O — association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Ann. Oncol. 30, v477–v478 (2019).

    Article  Google Scholar 

  57. 57.

    Bellone, M. & Calcinotto, A. Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes. Front. Oncol. 3, 231 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Beatty, G. L. & Moon, E. K. Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment. Oncoimmunology 3, e970027 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Sackstein, R., Schatton, T. & Barthel, S. R. T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab. Invest. 97, 669–697 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Slaney, C. Y., Kershaw, M. H. & Darcy, P. K. Trafficking of T cells into tumors. Cancer Res. 74, 7168–7174 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Lanitis, E., Dangaj, D., Irving, M. & Coukos, G. Mechanisms regulating T-cell infiltration and activity in solid tumors. Ann. Oncol. 28, xii18–xii32 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Teng, M. W., Ngiow, S. F., Ribas, A. & Smyth, M. J. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 75, 2139–2145 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Abastado, J. P. The next challenge in cancer immunotherapy: controlling T-cell traffic to the tumor. Cancer Res. 72, 2159–2161 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Hindley, J. P. et al. T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion. Cancer Res. 72, 5473–5482 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Lutsiak, M. E. et al. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105, 2862–2868 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Demaria, S. et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin. Cancer Res. 7, 3025–3030 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Nardin, A. et al. Dacarbazine promotes stromal remodeling and lymphocyte infiltration in cutaneous melanoma lesions. J. Invest. Dermatol. 131, 1896–1905 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Maxwell, M. B. & Maher, K. E. Chemotherapy-induced myelosuppression. Semin. Oncol. Nurs. 8, 113–123 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Javarappa, K. K., Tsallos, D. & Heckman, C. A. A multiplexed screening assay to evaluate chemotherapy-induced myelosuppression using healthy peripheral blood and bone marrow. SLAS Discov. 23, 687–696 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Osada, T. et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol. Immunother. 57, 1115–1124 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Ohm, J. E. et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101, 4878–4886 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Wallin, J. J. et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat. Commun. 7, 12624 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    US Food and Drug Administration. FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC. FDA https://www.fda.gov/drugs/fda-approves-atezolizumab-chemotherapy-and-bevacizumab-first-line-treatment-metastatic-non-squamous (2018).

  76. 76.

    The ASCO Post. FDA grants breakthrough therapy designation for atezolizumab/bevacizumab combination as first-line treatment for advanced or metastatic HCC. ASCO Post https://www.ascopost.com/News/59089 (2018).

  77. 77.

    Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    US Food and Drug Administration. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma (2020).

  79. 79.

    Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    US Food and Drug Administration. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma (2019).

  81. 81.

    Lanitis, E., Irving, M. & Coukos, G. Targeting the tumor vasculature to enhance T cell activity. Curr. Opin. Immunol. 33, 55–63 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Reichetzeder, C., Tsuprykov, O. & Hocher, B. Endothelin receptor antagonists in clinical research — lessons learned from preclinical and clinical kidney studies. Life Sci. 118, 141–148 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Kandalaft, L. E., Facciabene, A., Buckanovich, R. J. & Coukos, G. Endothelin B receptor, a new target in cancer immune therapy. Clin. Cancer Res. 15, 4521–4528 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Ott, P. A., Hodi, F. S. & Buchbinder, E. I. Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: an overview of rationale, preclinical evidence, and initial clinical data. Front. Oncol. 5, 202 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Yang, B. et al. The role of interleukin 17 in tumour proliferation, angiogenesis, and metastasis. Mediators Inflamm. 2014, 623759 (2014).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Deliyanti, D. et al. Foxp3+ Tregs are recruited to the retina to repair pathological angiogenesis. Nat. Commun. 8, 748 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. 87.

    Leung, O. M. et al. Regulatory T cells promote apelin-mediated sprouting angiogenesis in type 2 diabetes. Cell Rep. 24, 1610–1626 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Lugade, A. A. et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol. 174, 7516–7523 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89.

    Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Quezada, S. A. et al. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J. Exp. Med. 205, 2125–2138 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Peng, W. et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 72, 5209–5218 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Hong, M. et al. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 71, 6997–7009 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93.

    Muthuswamy, R. et al. NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res. 72, 3735–3743 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Harlin, H. et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Mulligan, A. M. et al. Tumoral lymphocytic infiltration and expression of the chemokine CXCL10 in breast cancers from the Ontario Familial Breast Cancer Registry. Clin. Cancer Res. 19, 336–346 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Kerkar, S. P. et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J. Clin. Invest. 121, 4746–4757 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Tsai, A. K. & Davila, E. Producer T cells: using genetically engineered T cells as vehicles to generate and deliver therapeutics to tumors. Oncoimmunology 5, e1122158 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Sasaki, K., Pardee, A. D., Okada, H. & Storkus, W. J. IL-4 inhibits VLA-4 expression on Tc1 cells resulting in poor tumor infiltration and reduced therapy benefit. Eur. J. Immunol. 38, 2865–2873 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Nakayama, F. et al. Expression of cutaneous lymphocyte-associated antigen regulated by a set of glycosyltransferases in human T cells: involvement of α1, 3-fucosyltransferase VII and β1,4-galactosyltransferase I. J. Invest. Dermatol. 115, 299–306 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Hu, J. et al. T-cell homing therapy for reducing regulatory T cells and preserving effector T-cell function in large solid tumors. Clin. Cancer Res. 24, 2920–2934 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Berraondo, P., Etxeberria, I., Ponz-Sarvise, M. & Melero, I. Revisiting interleukin-12 as a cancer immunotherapy agent. Clin. Cancer Res. 24, 2716–2718 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Kershaw, M. H. et al. Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum. Gene Ther. 13, 1971–1980 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Peng, W. et al. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin. Cancer Res. 16, 5458–5468 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Di Stasi, A. et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    Olofsson, P. S. et al. Blood pressure regulation by CD4+ lymphocytes expressing choline acetyltransferase. Nat. Biotechnol. 34, 1066–1071 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Cox, M. A. et al. Choline acetyltransferase-expressing T cells are required to control chronic viral infection. Science 363, 639–644 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Pellegrini, M. et al. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat. Med. 15, 528–536 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    Shimizu, T., Nomiyama, S., Hirata, F. & Hayaishi, O. Indoleamine 2,3-dioxygenase. Purification and some properties. J. Biol. Chem. 253, 4700–4706 (1978).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Moon, Y. W., Hajjar, J., Hwu, P. & Naing, A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunother. Cancer 3, 51 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Munn, D. H. & Mellor, A. L. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147–1154 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Weber, W. P. et al. Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines. Eur. J. Immunol. 36, 296–304 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Prendergast, G. C. et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol. Immunother. 63, 721–735 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Long, G. V. et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. J. Clin. Oncol. 36, 108 (2018).

    Article  Google Scholar 

  116. 116.

    Li, H. et al. Metabolomic adaptations and correlates of survival to immune checkpoint blockade. Nat. Commun. 10, 4346 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Luke, J. et al. Interferon γ (IFN-γ) gene signature and tryptophan 2,3-dioxygenase 2 (TDO2) gene expression: a potential predictive composite biomarker for linrodostat mesylate (BMS-986205; indoleamine 2,3-dioxygenase 1 inhibitor [IDO1i]) + nivolumab (NIVO). Ann. Oncol. 30, v760–v796 (2019).

    Article  Google Scholar 

  118. 118.

    Bradley, L. M., Haynes, L. & Swain, S. L. IL-7: maintaining T-cell memory and achieving homeostasis. Trends Immunol. 26, 172–176 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Shi, L. Z. et al. Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy. Nat. Commun. 7, 12335 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Pellegrini, M. et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144, 601–613 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Sportes, C. et al. Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin. Cancer Res. 16, 727–735 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Tian, Y. & Zajac, A. J. IL-21 and T cell differentiation: consider the context. Trends Immunol. 37, 557–568 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Pellegrini, M., Mak, T. W. & Ohashi, P. S. Fighting cancers from within: augmenting tumor immunity with cytokine therapy. Trends Pharmacol. Sci. 31, 356–363 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Punt, S. et al. A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17+ cell frequency. Cancer Immunol. Immunother. 65, 393–403 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Elsaesser, H., Sauer, K. & Brooks, D. G. IL-21 is required to control chronic viral infection. Science 324, 1569–1572 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Kurachi, M. et al. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat. Immunol. 15, 373–383 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Gu, Y. Z. et al. Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity. Sci. Rep. 6, 32351 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Sondergaard, H. et al. Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes. J. Immunother. 33, 236–249 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Mittal, D. et al. Improved treatment of breast cancer with anti-HER2 therapy requires interleukin-21 signaling in CD8+ T cells. Cancer Res. 76, 264–274 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  132. 132.

    Vallieres, F. & Girard, D. Mechanism involved in interleukin-21-induced phagocytosis in human monocytes and macrophages. Clin. Exp. Immunol. 187, 294–303 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Wan, C. K. et al. IL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells. Nat. Commun. 6, 7988 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Xue, L., Hickling, T., Song, R., Nowak, J. & Rup, B. Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody. Clin. Exp. Immunol. 183, 102–113 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. 135.

    Vegran, F. et al. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat. Immunol. 15, 758–766 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  142. 142.

    Jadhav, R. R. et al. Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Proc. Natl Acad. Sci. USA 116, 14113–14118 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Sonugur, F. G. & Akbulut, H. The role of tumor microenvironment in genomic instability of malignant tumors. Front. Genet. 10, 1063 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. 148.

    Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability — an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11, 220–228 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  149. 149.

    Thomas, R. et al. NY-ESO-1 based immunotherapy of cancer: current perspectives. Front. Immunol. 9, 947 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. 150.

    Whitehurst, A. W. Cause and consequence of cancer/testis antigen activation in cancer. Annu. Rev. Pharmacol. Toxicol. 54, 251–272 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Li, T. & Chen, Z. J. The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 215, 1287–1299 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Wang, H. et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc. Natl Acad. Sci. USA 114, 1637–1642 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  155. 155.

    Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Walker, A. J. et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol. Ther. 25, 2189–2201 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    D’Angelo, S. P. et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 c259T cells in synovial sarcoma. Cancer Discov. 8, 944–957 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  159. 159.

    Rupp, L. J. et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 737 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. 160.

    Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, eaba7365 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  161. 161.

    Crome, S. Q. et al. A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat. Med. 23, 368–375 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Schietinger, A., Delrow, J. J., Basom, R. S., Blattman, J. N. & Greenberg, P. D. Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state. Science 335, 723–727 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Tsukamoto, H. et al. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 78, 5011–5022 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  164. 164.

    Johnson, D. E., O’Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Stroud, C. R. et al. Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J. Oncol. Pharm. Pract. 25, 551–557 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  166. 166.

    Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  Google Scholar 

  168. 168.

    Godwin, J. W., Pinto, A. R. & Rosenthal, N. A. Macrophages are required for adult salamander limb regeneration. Proc. Natl Acad. Sci. USA 110, 9415–9420 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  169. 169.

    Lin, E. Y. & Pollard, J. W. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 67, 5064–5066 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  170. 170.

    Franklin, R. A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 344, 921–925 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Almand, B. et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J. Immunol. 166, 678–689 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  172. 172.

    Gonda, K. et al. Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer. Oncol. Lett. 14, 1766–1774 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. 173.

    Hayashi, T. et al. Peripheral blood monocyte count reflecting tumor-infiltrating macrophages is a predictive factor of adverse pathology in radical prostatectomy specimens. Prostate 77, 1383–1388 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  174. 174.

    Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Pollard, J. W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9, 259–270 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Ueno, T. et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin. Cancer Res. 6, 3282–3289 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Youn, J. I., Nagaraj, S., Collazo, M. & Gabrilovich, D. I. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 181, 5791–5802 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Qian, B. et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4, e6562 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  179. 179.

    Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Mendez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Ginhoux, F. & Jung, S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat. Rev. Immunol. 14, 392–404 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  183. 183.

    Liu, Y. & Cao, X. The origin and function of tumor-associated macrophages. Cell Mol. Immunol. 12, 1–4 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  184. 184.

    Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  185. 185.

    Laoui, D., Van Overmeire, E., De Baetselier, P., Van Ginderachter, J. A. & Raes, G. Functional relationship between tumor-associated macrophages and macrophage colony-stimulating factor as contributors to cancer progression. Front. Immunol. 5, 489 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  186. 186.

    Webb, S. E., Pollard, J. W. & Jones, G. E. Direct observation and quantification of macrophage chemoattraction to the growth factor CSF-1. J. Cell Sci. 109, 793–803 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Sasmono, R. T. et al. A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101, 1155–1163 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  188. 188.

    Zhu, Y. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74, 5057–5069 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Ngambenjawong, C., Gustafson, H. H. & Pun, S. H. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv. Drug Deliv. Rev. 114, 206–221 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. 190.

    Beck, A. H. et al. The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin. Cancer Res. 15, 778–787 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    Butowski, N. et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation early phase clinical trials consortium phase II study. Neuro Oncol. 18, 557–564 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  193. 193.

    Moskowitz, C. H. et al. CSF1R inhibition by PLX3397 in patients with relapsed or refractory Hodgkin lymphoma: results from a phase 2 single agent clinical trial. Blood 120, 1638–1638 (2012).

    Article  Google Scholar 

  194. 194.

    Collin, M. & Bigley, V. Human dendritic cell subsets: an update. Immunology 154, 3–20 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. 195.

    Kubli, S. P. et al. Fcmr regulates mononuclear phagocyte control of anti-tumor immunity. Nat. Commun. 10, 2678 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  196. 196.

    Lewis, C. E. & Pollard, J. W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605–612 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  197. 197.

    Lyford-Pike, S. et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 73, 1733–1741 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Yoon, K. W. Dead cell phagocytosis and innate immune checkpoint. BMB Rep. 50, 496–503 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Lewis, C. E., Harney, A. S. & Pollard, J. W. The multifaceted role of perivascular macrophages in tumors. Cancer Cell 30, 18–25 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. 201.

    Gronwall, C., Vas, J. & Silverman, G. J. Protective roles of natural IgM antibodies. Front. Immunol. 3, 66 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Voll, R. E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    CAS  Article  Google Scholar 

  203. 203.

    Voss, J. et al. Modulation of macrophage antitumor potential by apoptotic lymphoma cells. Cell Death Differ. 24, 971–983 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204.

    Ren, Y. et al. Apoptotic cells protect mice against lipopolysaccharide-induced shock. J. Immunol. 180, 4978–4985 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Correa, M. et al. Transient inflammatory response induced by apoptotic cells is an important mediator of melanoma cell engraftment and growth. Int. J. Cancer 114, 356–363 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  206. 206.

    Wermeling, F. et al. Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus. J. Exp. Med. 204, 2259–2265 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Tao, H. et al. Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J. Lipid Res. 56, 1449–1460 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. 208.

    Todt, J. C., Hu, B. & Curtis, J. L. The scavenger receptor SR-A I/II (CD204) signals via the receptor tyrosine kinase Mertk during apoptotic cell uptake by murine macrophages. J. Leukoc. Biol. 84, 510–518 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    Greenberg, M. E. et al. Oxidized phosphatidylserine–CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J. Exp. Med. 203, 2613–2625 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Georgoudaki, A. M. et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 15, 2000–2011 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  211. 211.

    Ferracini, M., Rios, F. J., Pecenin, M. & Jancar, S. Clearance of apoptotic cells by macrophages induces regulatory phenotype and involves stimulation of CD36 and platelet-activating factor receptor. Mediators Inflamm. 2013, 950273 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  212. 212.

    Ohtaki, Y. et al. Stromal macrophage expressing CD204 is associated with tumor aggressiveness in lung adenocarcinoma. J. Thorac. Oncol. 5, 1507–1515 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  213. 213.

    Cao, J. et al. Prognostic role of tumour-associated macrophages and macrophage scavenger receptor 1 in prostate cancer: a systematic review and meta-analysis. Oncotarget 8, 83261–83269 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  214. 214.

    Reinhold, M. I. et al. In vivo expression of alternatively spliced forms of integrin-associated protein (CD47). J. Cell Sci. 108, 3419–3425 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215.

    Murata, Y., Kotani, T., Ohnishi, H. & Matozaki, T. The CD47–SIRPα signalling system: its physiological roles and therapeutic application. J. Biochem. 155, 335–344 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  216. 216.

    Soto-Pantoja, D. R., Kaur, S. & Roberts, D. D. CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit. Rev. Biochem. Mol. Biol. 50, 212–230 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  217. 217.

    Brown, E., Hooper, L., Ho, T. & Gresham, H. Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins. J. Cell Biol. 111, 2785–2794 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  218. 218.

    Veillette, A. & Chen, J. SIRPα–CD47 immune checkpoint blockade in anticancer therapy. Trends Immunol. 39, 173–184 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  219. 219.

    Oldenborg, P. A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  220. 220.

    Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221.

    Barclay, A. N. & Van den Berg, T. K. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32, 25–50 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  222. 222.

    Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. 223.

    Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Willingham, S. B. et al. The CD47–signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl Acad. Sci. USA 109, 6662–6667 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  225. 225.

    Matlung, H. L., Szilagyi, K., Barclay, N. A. & van den Berg, T. K. The CD47–SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol. Rev. 276, 145–164 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  226. 226.

    Liu, J. et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS ONE 10, e0137345 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  227. 227.

    Sikic, B. I. et al. A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J. Clin. Oncol. 34, 3019–3019 (2016).

    Article  Google Scholar 

  228. 228.

    Narla, R. K. et al. Abstract 4694: the humanized anti-CD47 monclonal antibody, CC-90002, has antitumor activity in vitro and in vivo. Cancer Res. 77 (Suppl. 13), 4694 (2017).

    Google Scholar 

  229. 229.

    Advani, R. et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N. Engl. J. Med. 379, 1711–1721 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  230. 230.

    Kauder, S. E. et al. ALX148 is a high affinity Sirpα fusion protein that blocks CD47, enhances the activity of anti-cancer antibodies and checkpoint inhibitors, and has a favorable safety profile in preclinical models. Blood 130 (Suppl. 1), 112 (2017).

    Google Scholar 

  231. 231.

    Lakhani, N. J. et al. A phase 1 study of ALX148, a CD47 blocker, alone and in combination with established anticancer antibodies in patients with advanced malignancy and non-Hodgkin lymphoma. J. Clin. Oncol. 36, 3068 (2018).

    Article  Google Scholar 

  232. 232.

    Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  233. 233.

    Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  234. 234.

    Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  235. 235.

    Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  236. 236.

    Chanmee, T., Ontong, P., Konno, K. & Itano, N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 6, 1670–1690 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  237. 237.

    Vinnakota, K. et al. M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases. J. Cell Physiol. 232, 3468–3480 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  238. 238.

    Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  239. 239.

    De Palma, M. & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  240. 240.

    Alishekevitz, D. et al. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep. 17, 1344–1356 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  241. 241.

    McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  242. 242.

    Wang, X., Teng, F., Kong, L. & Yu, J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 9, 5023–5039 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  243. 243.

    Hicklin, D. J., Marincola, F. M. & Ferrone, S. HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol. Med. Today 5, 178–186 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  244. 244.

    Gubin, M. M. et al. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 175, 1014–1030 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  245. 245.

    Siu, L. L. et al. Safety and efficacy of durvalumab with or without tremelimumab in patients with PD-L1-low/negative recurrent or metastatic HNSCC: the phase 2 CONDOR randomized clinical trial. JAMA Oncol. 5, 195–203 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  246. 246.

    Licitra, L. F. et al. EAGLE: a phase 3, randomized, open-label study of durvalumab (D) with or without tremelimumab (T) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). J. Clin. Oncol. 37, 6012 (2019).

    Article  Google Scholar 

  247. 247.

    Rizvi, N. A. et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 6, 661–674 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  248. 248.

    Kowalski, D. M. et al. ARCTIC: durvalumab + tremelimumab and durvalumab monotherapy vs SoC in ≥ 3L advanced NSCLC treatment. Ann. Oncol. 29, viii493–viii494 (2018).

    Article  Google Scholar 

  249. 249.

    Planchard, D. et al. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann. Oncol. 31, 609–618 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  250. 250.

    Bazhenova, L. et al. A phase III randomized study of nivolumab plus ipilimumab versus nivolumab for previously treated patients with stage IV squamous cell lung cancer and no matching biomarker (Lung-MAP Sub-Study S1400I, NCT02785952). J. Clin. Oncol. 37, 9014 (2019).

    Article  Google Scholar 

  251. 251.

    Owonikoko, T. K. et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): results from the double-blind, randomized phase III CheckMate 451 study. Ann. Oncol. 30 (Suppl. 2), ii77–ii80 (2019).

    Article  Google Scholar 

  252. 252.

    Arance, A. M. et al. Combination treatment with cobimetinib (C) and atezolizumab (A) vs pembrolizumab (P) in previously untreated patients (pts) with BRAFV600 wild type (wt) advanced melanoma: primary analysis from the phase 3 IMspire170 trial. Ann. Oncol. 30, v851–v934 (2019).

    Article  Google Scholar 

  253. 253.

    Sanglier, T. et al. Use of trastuzumab emtansine (T-DM1; K) after pertuzumab + trastuzumab (PH) in patients with HER2-positive metastatic breast cancer (mBC): challenges in assessing effectiveness of treatment sequencing in the real world (RW). Ann. Oncol. 30, v104–v142 (2019).

    Article  Google Scholar 

  254. 254.

    O’Day, S. J., Hamid, O. & Urba, W. J. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 110, 2614–2627 (2007).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  255. 255.

    Poust, J. Targeting metastatic melanoma. Am. J. Health Syst. Pharm. 65, S9–S15 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  256. 256.

    Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  257. 257.

    Chemnitz, J. M., Parry, R. V., Nichols, K. E., June, C. H. & Riley, J. L. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  258. 258.

    Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  259. 259.

    Burnet, M. Cancer; a biological approach. I. The processes of control. Br. Med. J. 1, 779–786 (1957).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  260. 260.

    Thomas, L. in Cellular and Humoral Aspects of the Hypersensitive States (ed. Lawrence, H. S.) 529–532 (Hoeber-Harper, 1959).

  261. 261.

    Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  262. 262.

    Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  263. 263.

    Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  264. 264.

    Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  265. 265.

    Paley, M. A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  266. 266.

    Blackburn, S. D., Shin, H., Freeman, G. J. & Wherry, E. J. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl Acad. Sci. USA 105, 15016–15021 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  267. 267.

    Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  268. 268.

    Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  269. 269.

    Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  270. 270.

    Simpson, A. J., Caballero, O. L., Jungbluth, A., Chen, Y. T. & Old, L. J. Cancer/testis antigens, gametogenesis and cancer. Nat. Rev. Cancer 5, 615–625 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  271. 271.

    Leventhal, D. S. et al. Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells. Immunity 44, 847–859 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors thank M. Saunders for scientific editing of the Review and L. Vornholz for his intellectual and literary contribution to the section on T cell homing.

Author information

Affiliations

Authors

Contributions

All authors researched data for the article and reviewed and edited the manuscript before submission. S.P.K., T.B., L.L.S. and T.W.M. contributed to the discussion of content. S.P.K., T.B., D.V.A. and L.L.S. wrote the article.

Corresponding author

Correspondence to Tak W. Mak.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Drug Discovery thanks Daniel Chen, Yuval Shaked and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Tumour-infiltrating lymphocytes

(TILs). T cells bearing either CD4 or CD8 as well as B cells that are found in the tumour.

Cytotoxic T lymphocytes

(CTLs). T cells bearing the CD8 co-receptor that kill target cells by cytotoxic cytokine secretion, induction of apoptosis or induction of perforin–granzyme cytotoxicity.

T helper 1 cells

(TH1 cells). A specialized population of CD4+ T cells. They are important for immune responses against bacteria and viruses that invade cells, and are characterized by their production of interferon-γ.

Regulatory T cells

(Treg cells). FOXP3-expressing T cells that act indirectly to rein in the responses of effector T cells.

Progression-free survival

(PFS). The length of time during and after treatment that a patient lives with the cancer but it does not get worse.

Overall survival

(OS). The length of time from either the date of diagnosis or the start of treatment that patients remain alive.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). An immune effector function that occurs when antigen–antibody complexes bind to the Fc receptors of immune cells to trigger degranulation and destroy the entity.

Complement-dependent cytotoxicity

(CDC). The destruction of cells mediated by complement, which is a system of more than 30 soluble and membrane-bound proteins that act through a tightly regulated cascade of protein cleavage events to assemble the membrane attack complex in a target cell membrane.

Objective response rate

(ORR). The proportion of patients who have a partial or complete response to a therapy.

Chimeric antigen receptor (CAR) T cells

T cells that are genetically engineered to express a novel chimeric T cell receptor containing a portion of an antibody that recognizes an antigen on targeted tumour cells combined with the internal signalling apparatus of the T cell.

Adoptive cell transfer

The transfer or reinfusion of cells, most commonly by intravenous infusion.

Cancer-associated fibroblasts

Spindle-shaped cells within the tumour stroma that build up and remodel the extracellular matrix to support cancer growth.

Cytokine release syndrome

Pathology induced by a large, rapid release of cytokines into the blood by immune cells.

Exhausted T cells

(Tex cells). T cells that are phenotypically characterized by a progressive loss of effector function due to prolonged antigenic stimulation, such as occurs in chronic infections or cancer.

Common γ-chain

Cytokine receptor chain CD132, encoded by IL2RG; this chain is shared by the signalling complexes associated with receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

Cancer testis antigens

Proteins that are normally expressed solely in spermatogonia and spermatocytes but become aberrantly expressed in cancer cells owing to alterations to cancer cell methylomes.

TCR T cell

A T cell that has been genetically engineered to express a T cell receptor (TCR) with known specificity. In cancer, TCR T cells have been used to target known tumour antigens.

Angiogenic switch

A temporally and spatially restricted event during tumour progression in which proangiogenic factors facilitate the development of new capillary growth. These new vessels subsequently facilitate additional nutrient and waste exchange within the tumour to facilitate more rapid tumorigenesis.

Efferocytosis

The removal of dead and dying apoptotic cells by professional and non-professional phagocytes.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kubli, S.P., Berger, T., Araujo, D.V. et al. Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov (2021). https://doi.org/10.1038/s41573-021-00155-y

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing