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Understanding the tumor immune microenvironment (TIME) for effective therapy

Abstract

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

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Fig. 1: General classes of TIME.
Fig. 2: How tumor genotypes and phenotypes shape the TIME.
Fig. 3: Character of the TIME during progressive tumor development.

References

  1. 1.

    Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    CAS  PubMed  Google Scholar 

  2. 2.

    Ali, H. R., Chlon, L., Pharoah, P. D., Markowetz, F. & Caldas, C. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med. 13, e1002194 (2016).

    PubMed  Google Scholar 

  3. 3.

    Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015).

    CAS  PubMed  Google Scholar 

  4. 4.

    Aran, D., Hu, Z. & Butte, A. J. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 18, 220 (2017).

    PubMed  Google Scholar 

  5. 5.

    Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).

    CAS  PubMed  Google Scholar 

  6. 6.

    Mlecnik, B. et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44, 698–711 (2016).

    CAS  PubMed  Google Scholar 

  7. 7.

    Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    CAS  PubMed  Google Scholar 

  8. 8.

    Ademmer, K. et al. Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+CD18+ cells and CD8+CD103+ cells by multi-epitope imaging. Clin. Exp. Immunol. 112, 21–26 (1998).

    CAS  PubMed  Google Scholar 

  9. 9.

    Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 149, 201–210 (2015).

    CAS  PubMed  Google Scholar 

  10. 10.

    Spranger, S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int. Immunol. 28, 383–391 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Evans, R. A. et al. Lack of immunoediting in murine pancreatic cancer reversed with neoantigen. JCI Insight 1, e88328 (2016).

    PubMed Central  Google Scholar 

  12. 12.

    Lee, H. J. et al. Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer. J. Clin. Pathol. 69, 422–430 (2016).

    PubMed  Google Scholar 

  13. 13.

    Sautès-Fridman, C. et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front. Immunol. 7, 407 (2016).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Neyt, K., Perros, F., GeurtsvanKessel, C. H., Hammad, H. & Lambrecht, B. N. Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol. 33, 297–305 (2012).

    CAS  PubMed  Google Scholar 

  16. 16.

    Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Sumimoto, H., Imabayashi, F., Iwata, T. & Kawakami, Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J. Exp. Med. 203, 1651–1656 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    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  Google Scholar 

  19. 19.

    Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723.e714 (2017). 

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    CAS  PubMed  Google Scholar 

  23. 23.

    Qian, B.-Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015).

    CAS  PubMed  Google Scholar 

  25. 25.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Scholl, S. M. et al. Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J. Natl. Cancer Inst. 86, 120–126 (1994).

    CAS  PubMed  Google Scholar 

  28. 28.

    DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).

    CAS  PubMed  Google Scholar 

  30. 30.

    Khalili, J. S. et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin. Cancer Res. 18, 5329–5340 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Angelova, M. et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Becht, E. et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin. Cancer Res. 22, 4057–4066 (2016).

    CAS  PubMed  Google Scholar 

  35. 35.

    Gatalica, Z. et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol. Biomarkers Prev. 23, 2965–2970 (2014).

    CAS  PubMed  Google Scholar 

  36. 36.

    Boland, P. M. & Ma, W. W. Immunotherapy for colorectal cancer. Cancers (Basel) 9, E50 (2017).

    Google Scholar 

  37. 37.

    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  Google Scholar 

  38. 38.

    Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Kitamura, T., Qian, B.-Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Willimsky, G. & Blankenstein, T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437, 141–146 (2005).

    CAS  PubMed  Google Scholar 

  41. 41.

    Garbe, A. I. et al. Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses. Cancer Res. 66, 508–516 (2006).

    CAS  PubMed  Google Scholar 

  42. 42.

    DuPage, M. et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19, 72–85 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).

    CAS  PubMed  Google Scholar 

  45. 45.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    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  Google Scholar 

  47. 47.

    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  Google Scholar 

  48. 48.

    Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Bos, P. D., Plitas, G., Rudra, D., Lee, S. Y. & Rudensky, A. Y. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J. Exp. Med. 210, 2435–2466 (2013).

    PubMed  Google Scholar 

  51. 51.

    Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338.e6 (2017).

    CAS  PubMed  Google Scholar 

  52. 52.

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

    CAS  PubMed  Google Scholar 

  53. 53.

    Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

    CAS  PubMed  Google Scholar 

  54. 54.

    Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    CAS  PubMed  Google Scholar 

  55. 55.

    Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).

    CAS  Google Scholar 

  56. 56.

    Gunderson, A. J. et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6, 270–285 (2016).

    CAS  PubMed  Google Scholar 

  57. 57.

    Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Daley, D. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 23, 556–567 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Roberts, E. W. et al. Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    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  Google Scholar 

  61. 61.

    Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Sánchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov 6, 71–79 (2016).

    PubMed  Google Scholar 

  63. 63.

    Qian, B.-Z. et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J. Exp. Med. 212, 1433–1448 (2015).

    CAS  PubMed  Google Scholar 

  64. 64.

    Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).

    CAS  PubMed  Google Scholar 

  65. 65.

    Headley, M. B. et al. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531, 513–517 (2016).

    CAS  PubMed  Google Scholar 

  66. 66.

    Hanna, R. N. et al. Patrolling monocytes control tumor metastasis to the lung. Science 350, 985–990 (2015).

    CAS  PubMed  Google Scholar 

  67. 67.

    Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).

    CAS  PubMed  Google Scholar 

  68. 68.

    Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 17, 651–662 (2016).

    CAS  PubMed  Google Scholar 

  69. 69.

    Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Casbon, A.-J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. USA 112, E566–E575 (2015).

    CAS  PubMed  Google Scholar 

  71. 71.

    Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).

    CAS  PubMed  Google Scholar 

  72. 72.

    Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).

    CAS  PubMed  Google Scholar 

  73. 73.

    Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).

    CAS  PubMed  Google Scholar 

  74. 74.

    Kowanetz, M. et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc. Natl. Acad. Sci. USA 107, 21248–21255 (2010).

    CAS  PubMed  Google Scholar 

  75. 75.

    Jamieson, T. et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J. Clin. Invest. 122, 3127–3144 (2012).

    CAS  PubMed  Google Scholar 

  76. 76.

    Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014).

    CAS  PubMed  Google Scholar 

  77. 77.

    Koelwyn, G. J., Quail, D. F., Zhang, X., White, R. M. & Jones, L. W. Exercise-dependent regulation of the tumour microenvironment. Nat. Rev. Cancer 17, 620–632 (2017).

    PubMed  Google Scholar 

  78. 78.

    Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13, 875–887 (2013).

    CAS  PubMed  Google Scholar 

  79. 79.

    Julia, V., Macia, L. & Dombrowicz, D. The impact of diet on asthma and allergic diseases. Nat. Rev. Immunol. 15, 308–322 (2015).

    CAS  PubMed  Google Scholar 

  80. 80.

    Tall, A. R. & Yvan-Charvet, L. Cholesterol, inflammation and innate immunity. Nat. Rev. Immunol. 15, 104–116 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Robinson, D. P., Lorenzo, M. E., Jian, W. & Klein, S. L. Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses. PLoS Pathog. 7, e1002149 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Ridker, P. M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

    CAS  PubMed  Google Scholar 

  84. 84.

    Cook, N. R. et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. J. Am. Med. Assoc. 294, 47–55 (2005).

    CAS  Google Scholar 

  85. 85.

    Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378, 2081–2087 (2011).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    CAS  PubMed  Google Scholar 

  87. 87.

    Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790–802 (2010).

    CAS  PubMed  Google Scholar 

  88. 88.

    Waight, J. D., Hu, Q., Miller, A., Liu, S. & Abrams, S. I. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One 6, e27690 (2011).

    CAS  PubMed  Google Scholar 

  89. 89.

    Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358, eaal5081 (2017).

    PubMed  Google Scholar 

  90. 90.

    Cortez-Retamozo, V. et al. Angiotensin II drives the production of tumor-promoting macrophages. Immunity 38, 296–308 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Pucci, F. et al. PF4 promotes platelet production and lung cancer growth. Cell Rep. 17, 1764–1772 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Verschoor, C. P. et al. Blood CD33+HLA-DR myeloid-derived suppressor cells are increased with age and a history of cancer. J. Leukoc. Biol. 93, 633–637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Hale, M. et al. Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2. PLoS One 10, e0118784 (2015).

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Svoronos, N. et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov 7, 72–85 (2017).

    CAS  PubMed  Google Scholar 

  96. 96.

    Thompson, M. G., Peiffer, D. S., Larson, M., Navarro, F. & Watkins, S. K. FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice. Cancer Immunol. Immunother. 66, 615–625 (2017).

    CAS  PubMed  Google Scholar 

  97. 97.

    Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Kokolus, K. M. et al. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proc. Natl. Acad. Sci. USA 110, 20176–20181 (2013).

    CAS  PubMed  Google Scholar 

  100. 100.

    Kokolus, K. M. et al. Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naïve and tumor-bearing mice. Front. Immunol. 5, 23 (2014).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Flint, T. R. et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672–684 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525 (2016). e1512.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol. 13, 143–158 (2016).

    CAS  PubMed  Google Scholar 

  106. 106.

    Tsujikawa, T. et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep. 19, 203–217 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487–502.e15 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765.e17 (2017). 

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    CAS  PubMed  Google Scholar 

  111. 111.

    Wang, H. et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153, 910–918 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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Binnewies, M., Roberts, E.W., Kersten, K. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24, 541–550 (2018). https://doi.org/10.1038/s41591-018-0014-x

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