Review Article | Published:

Immunotherapy in colorectal cancer: rationale, challenges and potential


Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR–MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR–MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR–MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR–MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.

Key points

  • Colorectal cancer (CRC) can be categorized into tumours that are mismatch-repair-deficient or have high levels of microsatellite instability (dMMR–MSI-H; ~15%) and mismatch-repair-proficient or microsatellite instability-low tumours (pMMR–MSI-L; ~85%).

  • dMMR–MSI-H CRC is associated with a high tumour mutation burden and immune cell infiltration.

  • Immune checkpoint inhibitor (ICI) treatment, specifically with monoclonal antibodies targeting programmed cell death 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4), results in improved survival in metastatic dMMR–MSI-H CRC, but pMMR–MSI-L CRC is largely unresponsive to current ICIs.

  • The FDA has granted accelerated approval to the anti-PD1 antibodies pembrolizumab and nivolumab and to the combination of nivolumab with the anti-CTLA4 antibody ipilimumab for treatment of refractory dMMR–MSI-H CRC.

  • Clinical evaluation of ICIs in first-line metastatic, adjuvant and neoadjuvant settings and in combination with other therapies and research into improved prognostic and predictive biomarkers of ICI response and improved activity in pMMR–MSI-L CRC are ongoing.

  • Beyond PD1 blockade, monospecific and bispecific antibodies, cellular therapies, vaccines and cytokines targeting other immune checkpoint molecules, macrophages and other components of innate immunity are under active investigation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

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

Related links database:


  1. 1.

    Garborg, K. et al. Current status of screening for colorectal cancer. Ann. Oncol. 24, 1963–1972 (2013).

  2. 2.

    Siegel, R., Desantis, C. & Jemal, A. Colorectal cancer statistics, 2014. CA Cancer J. Clin. 64, 104–117 (2014).

  3. 3.

    Edwards, B. K. et al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 116, 544–573 (2010).

  4. 4.

    Sargent, D. et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J. Clin. Oncol. 27, 872–877 (2009).

  5. 5.

    Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

  6. 6.

    Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).

  7. 7.

    Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

  8. 8.

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

  9. 9.

    Pages, F. et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654–2666 (2005).

  10. 10.

    Galon, J., Fridman, W. H. & Pages, F. The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res. 67, 1883–1886 (2007).

  11. 11.

    Khalil, D. N., Smith, E. L., Brentjens, R. J. & Wolchok, J. D. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 13, 273–290 (2016).

  12. 12.

    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).

  13. 13.

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

  14. 14.

    Townsend, S. E. & Allison, J. P. Tumor rejection after direct costimulation of CD8+T cells by B7-transfected melanoma cells. Science 259, 368–370 (1993).

  15. 15.

    Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).

  16. 16.

    Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

  17. 17.

    Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

  18. 18.

    Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

  19. 19.

    Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

  20. 20.

    Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

  21. 21.

    Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

  22. 22.

    Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

  23. 23.

    Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

  24. 24.

    Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

  25. 25.

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

  26. 26.

    Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

  27. 27.

    Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

  28. 28.

    The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  29. 29.

    Salipante, S. J., Scroggins, S. M., Hampel, H. L., Turner, E. H. & Pritchard, C. C. Microsatellite instability detection by next generation sequencing. Clin. Chem. 60, 1192–1199 (2014).

  30. 30.

    Niu, B. et al. MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics 30, 1015–1016 (2014).

  31. 31.

    Middha, S. et al. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data. JCO Precis. Oncol. 1, 1–17 (2017).

  32. 32.

    Hause, R. J., Pritchard, C. C., Shendure, J. & Salipante, S. J. Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22, 1342–1350 (2016).

  33. 33.

    Giardiello, F. M. et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 147, 502–526 (2014).

  34. 34.

    Alexander, J. et al. Histopathological identification of colon cancer with microsatellite instability. Am. J. Pathol. 158, 527–535 (2001).

  35. 35.

    Dolcetti, R. et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am. J. Pathol. 154, 1805–1813 (1999).

  36. 36.

    Smyrk, T. C., Watson, P., Kaul, K. & Lynch, H. T. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 91, 2417–2422 (2001).

  37. 37.

    Young, J. et al. Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am. J. Pathol. 159, 2107–2116 (2001).

  38. 38.

    Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

  39. 39.

    Llosa, N. J. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43–51 (2015).

  40. 40.

    Graham, D. M. & Appelman, H. D. Crohn’s-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod. Pathol. 3, 332–335 (1990).

  41. 41.

    Jass, J. R. et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut 42, 673–679 (1998).

  42. 42.

    Nagorsen, D. et al. Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T cell response against tumor-associated antigens and survival. J. Transl Med. 5, 62 (2007).

  43. 43.

    Boland, C. R. et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 58, 5248–5257 (1998).

  44. 44.

    Popat, S., Hubner, R. & Houlston, R. S. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 23, 609–618 (2005).

  45. 45.

    Venderbosch, S. et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin. Cancer Res. 20, 5322–5330 (2014).

  46. 46.

    Chung, K. Y. et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J. Clin. Oncol. 28, 3485–3490 (2010).

  47. 47.

    Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

  48. 48.

    Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

  49. 49.

    Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

  50. 50.

    Lipson, E. J. et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin. Cancer Res. 19, 462–468 (2013).

  51. 51.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

  52. 52.

    Le, D. T. et al. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. J. Clin. Oncol. 34, 103 (2016).

  53. 53.

    Overman, M. J. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017).

  54. 54.

    Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).

  55. 55.

    Andre, T. L. et al. Nivolumab+ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142. J. Clin. Oncol. 36 (Suppl.), 553 (2018).

  56. 56.

    Lenz, H.-J. J. et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann. Oncol. 29 (Suppl.), LBA18_PR (2018).

  57. 57.

    US National Library of Medicine. (2019).

  58. 58.

    US National Library of Medicine. (2018).

  59. 59.

    Liu, L. et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin. Cancer Res. 21, 1639–1651 (2015).

  60. 60.

    Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).

  61. 61.

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

  62. 62.

    Bendell, J. C. B. et al. A phase 1b study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC). J. Clin. Oncol. 36, 560 (2018).

  63. 63.

    US National Library of Medicine. (2019).

  64. 64.

    Bendell, J. et al. Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy versus regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann. Oncol. 29, LBA–004 (2018).

  65. 65.

    US National Library of Medicine. (2018).

  66. 66.

    US National Library of Medicine. (2019).

  67. 67.

    US National Library of Medicine. (2019).

  68. 68.

    US National Library of Medicine. (2019).

  69. 69.

    Segal, N. H. S. et al. Phase-I studies of the novel carcinoembryonic antigen T cell bispecific (CEA-CD3 TCB) antibody as a single agent and in combination with atezolizumab. Ann. Oncol. 28 (Suppl. 5), 122–141 (2017).

  70. 70.

    Pfirschke, C. et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44, 343–354 (2016).

  71. 71.

    Hodi, F. S. et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol. Res. 2, 632–642 (2014).

  72. 72.

    Hochster, H. S. B. et al. Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). J. Clin. Oncol. 35 (Suppl.), 673 (2017).

  73. 73.

    Bendell, J. C. et al. Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC). J. Clin. Oncol. 33, 704 (2015).

  74. 74.

    Wallin, J. et al. Clinical activity and immune correlates from a phase Ib study evaluating atezolizumab (anti-PDL1) in combination with FOLFOX and bevacizumab (anti-VEGF) in metastatic colorectal carcinoma. Cancer Res. 76, 2651 (2016).

  75. 75.

    Park, S. S. et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol. Res. 3, 610–619 (2015).

  76. 76.

    Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

  77. 77.

    US National Library of Medicine. (2018).

  78. 78.

    Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

  79. 79.

    Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

  80. 80.

    Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

  81. 81.

    Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

  82. 82.

    Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).

  83. 83.

    Li, B. et al. Landscape of tumor-infiltrating T cell repertoire of human cancers. Nat. Genet. 48, 725–732 (2016).

  84. 84.

    McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

  85. 85.

    Anagnostou, V. et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 7, 264–276 (2017).

  86. 86.

    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).

  87. 87.

    Pages, F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).

  88. 88.

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

  89. 89.

    Yaeger, R. et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell 33, 125–136 (2018).

  90. 90.

    Palles, C. et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45, 136–144 (2013).

  91. 91.

    Elsayed, F. A. et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur. J. Hum. Genet. 23, 1080–1084 (2015).

  92. 92.

    Jansen, A. M. et al. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. Eur. J. Hum. Genet. 24, 1089–1092 (2016).

  93. 93.

    Domingo, E. et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol. Hepatol. 1, 207–216 (2016).

  94. 94.

    US National Library of Medicine. (2018).

  95. 95.

    US National Library of Medicine. (2018).

  96. 96.

    US National Library of Medicine. (2019).

  97. 97.

    Hersom, M. & Jorgensen, J. T. Companion and complementary diagnostics-focus on PD-L1 expression assays for PD-1/PD-L1 checkpoint inhibitors in NSCLC. Ther. Drug Monit. 40, 9–16 (2017).

  98. 98.

    André, T. et al. Analysis of tumor PD-L1 expression and biomarkers in relation to clinical activity in patients (pts) with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab (NIVO) + ipilimumab (IPI): CheckMate 142. Ann. Oncol. 28, 484PD (2017).

  99. 99.

    Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

  100. 100.

    Koelzer, V. H., Baker, K., Kassahn, D., Baumhoer, D. & Zlobec, I. Prognostic impact of beta-2-microglobulin expression in colorectal cancers stratified by mismatch repair status. J. Clin. Pathol. 65, 996–1002 (2012).

  101. 101.

    Shin, D. S. et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017).

  102. 102.

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

  103. 103.

    Chifman, J., Pullikuth, A., Chou, J. W., Bedognetti, D. & Miller, L. D. Conservation of immune gene signatures in solid tumors and prognostic implications. BMC Cancer 16, 911 (2016).

  104. 104.

    Sinicrope, F. A. O. et al. Randomized trial of FOLFOX alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair or microsatellite instability (ATOMIC, Alliance A021502). J. Clin. Oncol. 35, TPS3630 (2017).

  105. 105.

    US National Library of Medicine. (2019).

  106. 106.

    Grootscholten, C. et al. Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Ann. Oncol. 29, LBA37_PR (2018).

  107. 107.

    Watson, P. et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int. J. Cancer 123, 444–449 (2008).

  108. 108.

    Syngal, S. et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 110, 223–262; quiz 263 (2015).

  109. 109.

    Schwitalle, Y. et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134, 988–997 (2008).

  110. 110.

    Kloor, M. & von Knebel Doeberitz, M. The immune biology of microsatellite-unstable cancer. Trends Cancer 2, 121–133 (2016).

  111. 111.

    Reuschenbach, M. et al. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome. Fam. Cancer 9, 173–179 (2010).

  112. 112.

    Doeberitz, M. v. K. et al. Frameshift peptide neoantigens as vaccine targets in microsatellite-unstable cancers. Cancer Immunol. Res. 4, A006 (2016).

  113. 113.

    Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

  114. 114.

    Grosso, J. F. et al. LAG-3 regulates CD8+T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 117, 3383–3392 (2007).

  115. 115.

    Ngiow, S. F. et al. Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71, 3540–3551 (2011).

  116. 116.

    Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).

  117. 117.

    Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

  118. 118.

    Ward-Kavanagh, L. K., Lin, W. W., Sedy, J. R. & Ware, C. F. The TNF receptor superfamily in co-stimulating and co-inhibitory responses. Immunity 44, 1005–1019 (2016).

  119. 119.

    Croft, M., Benedict, C. A. & Ware, C. F. Clinical targeting of the TNF and TNFR superfamilies. Nat. Rev. Drug Discov. 12, 147–168 (2013).

  120. 120.

    Brenner, D., Blaser, H. & Mak, T. W. Regulation of tumour necrosis factor signalling: live or let die. Nat. Rev. Immunol. 15, 362–374 (2015).

  121. 121.

    Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

  122. 122.

    Miliotou, A. N. & Papadopoulou, L. C. CAR T cell therapy: a new era in cancer immunotherapy. Curr. Pharm. Biotechnol. 19, 5–18 (2018).

  123. 123.

    Yeku, O. O. & Brentjens, R. J. Armored CAR T cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T cell anti-tumour efficacy. Biochem. Soc. Trans. 44, 412–418 (2016).

  124. 124.

    Shum, T., Kruse, R. L. & Rooney, C. M. Strategies for enhancing adoptive T cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities. Expert Opin. Biol. Ther. 18, 653–664 (2018).

  125. 125.

    Parkhurst, M. R. et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620–626 (2011).

  126. 126.

    Katz, S. C. et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T cell therapy for CEA+liver metastases. Clin. Cancer Res. 21, 3149–3159 (2015).

  127. 127.

    Zhang, C. et al. Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers. Mol. Ther. 25, 1248–1258 (2017).

  128. 128.

    Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).

  129. 129.

    Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

  130. 130.

    Kochenderfer, J. N. et al. Chemotherapy-refractory diffuse large B cell lymphoma and indolent B cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2015).

  131. 131.

    Johnson, L. A. & June, C. H. Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 27, 38–58 (2017).

  132. 132.

    Newick, K., O’Brien, S., Moon, E. & Albelda, S. M. CAR T cell therapy for solid tumors. Annu. Rev. Med. 68, 139–152 (2017).

  133. 133.

    Hoover, H. C. Jr. et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial. J. Clin. Oncol. 11, 390–399 (1993).

  134. 134.

    Harris, J. E. et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J. Clin. Oncol. 18, 148–157 (2000).

  135. 135.

    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).

  136. 136.

    Lin, H. et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320, 807–811 (2008).

  137. 137.

    Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat. Immunol. 10, 734–743 (2009).

  138. 138.

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

  139. 139.

    US National Library of Medicine. (2019).

  140. 140.

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

  141. 141.

    Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).

  142. 142.

    Arlauckas, S. P. et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci. Transl Med. 9, eaal3604 (2017).

  143. 143.

    Ablasser, A. et al. cGAS produces a 2′;-5′;-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

  144. 144.

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

  145. 145.

    Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015).

  146. 146.

    US National Library of Medicine. (2018).

  147. 147.

    US National Library of Medicine. (2019).

  148. 148.

    US National Library of Medicine. (2018).

  149. 149.

    Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

  150. 150.

    Freeman-Keller, M. et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin. Cancer Res. 22, 886–894 (2016).

  151. 151.

    Lo, J. A., Fisher, D. E. & Flaherty, K. T. Prognostic significance of cutaneous adverse events associated with pembrolizumab therapy. JAMA Oncol. 1, 1340–1341 (2015).

  152. 152.

    Boland, P. M. & Ma, W. W. Immunotherapy for colorectal cancer. Cancers 9, 50 (2017).

Download references

Reviewer information

Nature Reviews Gastroenterology & Hepatology thanks T. André, J. Lee and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Author information

K.G., Z.K.S., A.C., R.B.M. and N.H.S. researched data for the article. K.G., Z.K.S., A.C., J.S., N.H.S. and L.A.D. made substantial contributions to discussion of the article content. K.G., Z.K.S., A.C., R.B.M., J.S. and N.H.S. wrote the manuscript. K.G., Z.K.S., N.H.S. and L.A.D. reviewed and/or edited the manuscript before submission.

Competing interests

R.B.M. is a speaker for Vindico and Medscape and a consultant for Roche. N.H.S. receives research funding from Roche/Genentech, Merck, Bristol-Myers Squibb, MedImmune/AstraZeneca and Incyte and is on the advisory board of Roche/Genentech, Merck, Bristol-Myers Squibb, MedImmune/AstraZeneca, Boehringer Ingelheim and Pfizer. L.A.D. is a founder and shareholder of PapGene and Personal Genome Diagnostics (PGDx) and a consultant for Merck, PGDx and Phoremost. PapGene and PGDx, as well as other companies, have licensed technologies from Johns Hopkins University on which L.A.D. is an inventor. These licences and relationships are associated with equity or royalty payments to L.A.D. L.A.D. is also a member of the board of directors of PGDx and Jounce Therapeutics. The terms of these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. K.G., Z.K.S., A.C. and J.S. declare no competing interests.

Correspondence to Karuna Ganesh.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: Targets of currently FDA-approved immune checkpoint inhibitors.
Fig. 2: The tumour microenvironment of dMMR–MSI-H and pMMR–MSI-L CRC.
Fig. 3: Targets of select immunomodulatory drugs in clinical trials for metastatic CRC.