1932

Abstract

Immune checkpoint inhibitors (ICIs) have made an indelible mark in the field of cancer immunotherapy. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, ICIs—which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)—quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival. However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. Ultimately, by building on these insights, researchers should be able to combine ICIs with other agents, or design new immunotherapies, to achieve broader and more durable efficacy as well as greater safety. Here, we review the history and clinical utility of ICIs, the mechanisms of resistance to therapy, and local and systemic immune cell changes associated with outcome.

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2021-01-24
2024-10-04
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Literature Cited

  1. 1. 
    Valk E, Rudd CE, Schneider H 2008. CTLA-4 trafficking and surface expression. Trends Immunol 29:6272–79
    [Google Scholar]
  2. 2. 
    Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ et al. 1994. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:5405–13
    [Google Scholar]
  3. 3. 
    Krummel MF, Allison JP. 1995. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182:2459–65
    [Google Scholar]
  4. 4. 
    Linsley PS, Clark EA, Ledbetter JA 1990. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. PNAS 87:135031–35
    [Google Scholar]
  5. 5. 
    Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA 1991. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J. Exp. Med. 173:3721–30
    [Google Scholar]
  6. 6. 
    Azuma M, Ito D, Yagita H, Okumura K, Phillips JH et al. 1993. B70 antigen is a second ligand for CTLA-4 and CD28. Nature 366:645076–79
    [Google Scholar]
  7. 7. 
    Valk E, Leung R, Kang H, Kaneko K, Rudd CE, Schneider H 2006. T cell receptor-interacting molecule acts as a chaperone to modulate surface expression of the CTLA-4 coreceptor. Immunity 25:5807–21
    [Google Scholar]
  8. 8. 
    Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA 1991. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174:3561–69
    [Google Scholar]
  9. 9. 
    Chuang E, Fisher TS, Morgan RW, Robbins MD, Duerr JM et al. 2000. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 13:3313–22
    [Google Scholar]
  10. 10. 
    Chuang E, Lee K-M, Robbins MD, Duerr JM, Alegre M-L et al. 1999. Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases. J. Immunol. 162:31270–77
    [Google Scholar]
  11. 11. 
    Lee K-M, Chuang E, Griffin M, Khattri R, Hong DK et al. 1998. Molecular basis of T cell inactivation by CTLA-4. Science 282:53972263–66
    [Google Scholar]
  12. 12. 
    Marengère LEM, Waterhouse P, Duncan GS, Mittrücker H-W, Feng G-S, Mak TW 1996. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272:52651170–73
    [Google Scholar]
  13. 13. 
    Fraser JH, Rincón M, McCoy KD, Le Gros G 1999. CTLA4 ligation attenuates AP-1, NFAT and NF-κB activity in activated T cells. Eur. J. Immunol. 29:3838–44
    [Google Scholar]
  14. 14. 
    Olsson C, Riebeck K, Dohlsten M, Michaëlsson E 1999. CTLA-4 ligation suppresses CD28-induced NF-κB and AP-1 activity in mouse T cell blasts. J. Biol. Chem. 274:2014400–5
    [Google Scholar]
  15. 15. 
    Hoff H, Kolar P, Ambach A, Radbruch A, Brunner-Weinzierl MC 2010. CTLA-4 (CD152) inhibits T cell function by activating the ubiquitin ligase Itch. Mol. Immunol. 47:101875–81
    [Google Scholar]
  16. 16. 
    Masteller EL, Chuang E, Mullen AC, Reiner SL, Thompson CB 2000. Structural analysis of CTLA-4 function in vivo. J. Immunol. 164:105319–27
    [Google Scholar]
  17. 17. 
    Read S, Malmström V, Powrie F 2000. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192:2295–302
    [Google Scholar]
  18. 18. 
    Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J et al. 2000. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192:2303–10
    [Google Scholar]
  19. 19. 
    Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D et al. 2006. Blockade of CTLA-4 on CD4+ CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177:74376–83
    [Google Scholar]
  20. 20. 
    Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M et al. 2008. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:5899271–75
    [Google Scholar]
  21. 21. 
    Friedline RH, Brown DS, Nguyen H, Kornfeld H, Lee J et al. 2009. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J. Exp. Med. 206:2421–34
    [Google Scholar]
  22. 22. 
    Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA 2006. TGF-β requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J. Immunol. 176:63321–29
    [Google Scholar]
  23. 23. 
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:5541–47
    [Google Scholar]
  24. 24. 
    Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A et al. 1995. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:5238985–88
    [Google Scholar]
  25. 25. 
    Chambers CA, Sullivan TJ, Allison JP 1997. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7:6885–95
    [Google Scholar]
  26. 26. 
    Leach DR, Krummel MF, Allison JP 1996. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:52561734–36
    [Google Scholar]
  27. 27. 
    Kwon ED, Hurwitz AA, Foster BA, Madias C, Feldhaus AL et al. 1997. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. PNAS 94:158099–103
    [Google Scholar]
  28. 28. 
    Yang YF, Zou JP, Mu J, Wijesuriya R, Ono S et al. 1997. Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: The effect is manifested only at the restricted tumor-bearing stages. Cancer Res 57:184036–41
    [Google Scholar]
  29. 29. 
    Hurwitz AA, Townsend SE, Yu TF, Wallin JA, Allison JP 1998. Enhancement of the anti-tumor immune response using a combination of interferon-γ and B7 expression in an experimental mammary carcinoma. Int. J. Cancer 77:1107–13
    [Google Scholar]
  30. 30. 
    van Elsas A, Hurwitz AA, Allison JP 1999. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190:3355–66
    [Google Scholar]
  31. 31. 
    Hurwitz AA, Yu TF, Leach DR, Allison JP 1998. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. PNAS 95:1710067–71
    [Google Scholar]
  32. 32. 
    Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363:8711–23
    [Google Scholar]
  33. 33. 
    Ishida Y, Agata Y, Shibahara K, Honjo T 1992. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:113887–95
    [Google Scholar]
  34. 34. 
    Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME et al. 2009. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114:81537–44
    [Google Scholar]
  35. 35. 
    Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M et al. 2019. PD‐1/PD‐L1 pathway: basic biology and role in cancer immunotherapy. J. Cell Physiol. 234:1016824–37
    [Google Scholar]
  36. 36. 
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192:71027–34
    [Google Scholar]
  37. 37. 
    Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M et al. 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2:3261–68
    [Google Scholar]
  38. 38. 
    Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T 2001. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting Src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 98:2413866–71
    [Google Scholar]
  39. 39. 
    Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA et al. 2004. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett 574:1–337–41
    [Google Scholar]
  40. 40. 
    Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA 2012. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci. Signal. 5:230ra46
    [Google Scholar]
  41. 41. 
    Nishimura H, Minato N, Nakano T, Honjo T 1998. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 10:101563–72
    [Google Scholar]
  42. 42. 
    Nishimura H, Nose M, Hiai H, Minato N, Honjo T 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:2141–51
    [Google Scholar]
  43. 43. 
    Nishimura H. 2001. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:5502319–22
    [Google Scholar]
  44. 44. 
    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N 2002. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. PNAS 99:1912293–97
    [Google Scholar]
  45. 45. 
    Hirano F, Kaneko K, Tamura H, Dong H, Wang S et al. 2005. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65:31089–96
    [Google Scholar]
  46. 46. 
    Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P et al. 2003. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9:5562–67
    [Google Scholar]
  47. 47. 
    He Y-F, Zhang G-M, Wang X-H, Zhang H, Yuan Y et al. 2004. Blocking programmed death-1 ligand-PD-1 interactions by local gene therapy results in enhancement of antitumor effect of secondary lymphoid tissue chemokine. J. Immunol. 173:84919–28
    [Google Scholar]
  48. 48. 
    Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y et al. 2004. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64:31140–45
    [Google Scholar]
  49. 49. 
    Iwai Y. 2004. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int. Immunol. 17:2133–44
    [Google Scholar]
  50. 50. 
    Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H et al. 2004. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. PNAS 101:4917174–79
    [Google Scholar]
  51. 51. 
    Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM et al. 2006. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 66:73381–85
    [Google Scholar]
  52. 52. 
    Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K et al. 2005. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin. Cancer Res. 11:82947–53
    [Google Scholar]
  53. 53. 
    Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S 2007. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 56:81173–82
    [Google Scholar]
  54. 54. 
    Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y et al. 2007. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. PNAS 104:93360–65
    [Google Scholar]
  55. 55. 
    Nomi T, Sho M, Akahori T, Hamada K, Kubo A et al. 2007. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13:72151–57
    [Google Scholar]
  56. 56. 
    Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML et al. 2007. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin. Cancer Res. 13:61757–61
    [Google Scholar]
  57. 57. 
    Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O et al. 2014. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384:99481109–17
    [Google Scholar]
  58. 58. 
    Robert C, Schachter J, Long GV, Arance A, Grob JJ et al. 2015. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372:262521–32
    [Google Scholar]
  59. 59. 
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL et al. 2015. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373:123–34
    [Google Scholar]
  60. 60. 
    Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T et al. 2016. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375:191823–33
    [Google Scholar]
  61. 61. 
    Remark R, Becker C, Gomez JE, Damotte D, Dieu-Nosjean M-C et al. 2015. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am. J. Respir. Crit. Care Med. 191:4377–90
    [Google Scholar]
  62. 62. 
    Marcus L, Lemery SJ, Keegan P, Pazdur R 2019. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin. Cancer Res. 25:133753–58
    [Google Scholar]
  63. 63. 
    Mayoux M, Roller A, Pulko V, Sammicheli S, Chen S et al. 2020. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci. Transl. Med. 12:534eaav7431
    [Google Scholar]
  64. 64. 
    Akinleye A, Rasool Z. 2019. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J. Hematol. Oncol. 12:192
    [Google Scholar]
  65. 65. 
    Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV et al. 2016. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:100311909–20
    [Google Scholar]
  66. 66. 
    West H, McCleod M, Hussein M, Morabito A, Rittmeyer A et al. 2019. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:7924–37
    [Google Scholar]
  67. 67. 
    Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D et al. 2018. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378:242288–301
    [Google Scholar]
  68. 68. 
    Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M et al. 2018. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379:232220–29
    [Google Scholar]
  69. 69. 
    Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH et al. 2018. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379:222108–21
    [Google Scholar]
  70. 70. 
    Powles T, O'Donnell PH, Massard C, Arkenau H-T, Friedlander TW et al. 2017. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 3:9e172411
    [Google Scholar]
  71. 71. 
    Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D et al. 2017. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J. Clin. Oncol. 35:192117–24
    [Google Scholar]
  72. 72. 
    Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M et al. 2018. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19:151–64
    [Google Scholar]
  73. 73. 
    Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P et al. 2016. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17:101374–85
    [Google Scholar]
  74. 74. 
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS et al. 2015. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372:212018–28
    [Google Scholar]
  75. 75. 
    Ott PA, Bang Y-J, Piha-Paul SA, Razak ARA, Bennouna J et al. 2019. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J. Clin. Oncol. 37:4318–27
    [Google Scholar]
  76. 76. 
    Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM et al. 2017. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 129:233071–73
    [Google Scholar]
  77. 77. 
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H et al. 2015. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372:262509–20
    [Google Scholar]
  78. 78. 
    Ribas A, Wolchok JD. 2018. Cancer immunotherapy using checkpoint blockade. Science 359:63821350–55
    [Google Scholar]
  79. 79. 
    Haslam A, Prasad V. 2019. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw. Open 2:5e192535
    [Google Scholar]
  80. 80. 
    Daud AI, Wolchok JD, Robert C, Hwu W-J, Weber JS et al. 2016. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J. Clin. Oncol. 34:344102–9
    [Google Scholar]
  81. 81. 
    Stenehjem DD, Tran D, Nkrumah MA, Gupta S 2018. PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer. OncoTargets Ther 11:5973–89
    [Google Scholar]
  82. 82. 
    Yearley JH, Gibson C, Yu N, Moon C, Murphy E et al. 2017. PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin. Cancer Res. 23:123158–67
    [Google Scholar]
  83. 83. 
    Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM et al. 2017. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16:112598–608
    [Google Scholar]
  84. 84. 
    Cristescu R, Mogg R, Ayers M, Albright A, Murphy E et al. 2018. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362:6411eaar3593
    [Google Scholar]
  85. 85. 
    Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C et al. 2015. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350:6257207–11
    [Google Scholar]
  86. 86. 
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V et al. 2015. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:6230124–28
    [Google Scholar]
  87. 87. 
    Boyiadzis MM, Kirkwood JM, Marshall JL, Pritchard CC, Azad NS, Gulley JL 2018. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J. Immunother. Cancer 6:135
    [Google Scholar]
  88. 88. 
    Maleki Vareki S. 2018. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J. Immunother. Cancer 6:1157
    [Google Scholar]
  89. 89. 
    Kaufman HL, Russell JS, Hamid O, Bhatia S, Terheyden P et al. 2018. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J. Immunother. Cancer 6:17
    [Google Scholar]
  90. 90. 
    Ni L, Lu J. 2018. Interferon gamma in cancer immunotherapy. Cancer Med 7:94509–16
    [Google Scholar]
  91. 91. 
    Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S et al. 2018. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity 49:61148–61.e7
    [Google Scholar]
  92. 92. 
    Karachaliou N, Gonzalez-Cao M, Crespo G, Drozdowskyj A, Aldeguer E et al. 2018. Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther. Adv. Med. Oncol. 10:1758834017749748
    [Google Scholar]
  93. 93. 
    Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A et al. 2017. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Investig. 127:82930–40
    [Google Scholar]
  94. 94. 
    Gao J, Shi LZ, Zhao H, Chen J, Xiong L et al. 2016. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167:2397–404.e9
    [Google Scholar]
  95. 95. 
    Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S et al. 2017. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 7:2188–201
    [Google Scholar]
  96. 96. 
    Huang L, Malu S, McKenzie JA, Andrews MC, Talukder AH et al. 2018. The RNA-binding protein MEX3B mediates resistance to cancer immunotherapy by downregulating HLA-A expression. Clin. Cancer Res. 24:143366–76
    [Google Scholar]
  97. 97. 
    Rodig SJ, Gusenleitner D, Jackson DG, Gjini E, Giobbie-Hurder A et al. 2018. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl. Med. 10:450eaar3342
    [Google Scholar]
  98. 98. 
    Nowicki TS, Hu-Lieskovan S, Ribas A 2018. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J 24:147–53
    [Google Scholar]
  99. 99. 
    Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N et al. 2015. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:62641079–84
    [Google Scholar]
  100. 100. 
    Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC et al. 2018. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359:637197–103
    [Google Scholar]
  101. 101. 
    Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT et al. 2018. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:637191–97
    [Google Scholar]
  102. 102. 
    Tinsley N, Zhou C, Tan G, Rack S, Lorigan P et al. 2020. Cumulative antibiotic use significantly decreases efficacy of checkpoint inhibitors in patients with advanced cancer. Oncologist 25:155–63
    [Google Scholar]
  103. 103. 
    Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M et al. 2018. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann. Oncol. 29:61437–44
    [Google Scholar]
  104. 104. 
    Shen J, Ju Z, Zhao W, Wang L, Peng Y et al. 2018. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24:5556–62
    [Google Scholar]
  105. 105. 
    Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE et al. 2018. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359:6377770–75
    [Google Scholar]
  106. 106. 
    Keenan TE, Burke KP, Van Allen EM 2019. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 25:3389–402
    [Google Scholar]
  107. 107. 
    Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S et al. 2015. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:7577249–53
    [Google Scholar]
  108. 108. 
    Marwitz S, Scheufele S, Perner S, Reck M, Ammerpohl O, Goldmann T 2017. Epigenetic modifications of the immune-checkpoint genes CTLA4 and PDCD1 in non-small cell lung cancer results in increased expression. Clin. Epigenet. 9:51
    [Google Scholar]
  109. 109. 
    Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J et al. 2016. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:63161160–65
    [Google Scholar]
  110. 110. 
    Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W et al. 2016. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375:9819–29
    [Google Scholar]
  111. 111. 
    Gettinger S, Choi J, Hastings K, Truini A, Datar I et al. 2017. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov 7:121420–35
    [Google Scholar]
  112. 112. 
    George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ et al. 2017. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46:2197–204
    [Google Scholar]
  113. 113. 
    Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R et al. 2017. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov 7:3264–76
    [Google Scholar]
  114. 114. 
    Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M et al. 2019. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 16:9563–80
    [Google Scholar]
  115. 115. 
    Bajwa R, Cheema A, Khan T, Amirpour A, Paul A et al. 2019. Adverse effects of immune checkpoint inhibitors (programmed death-1 inhibitors and cytotoxic T-lymphocyte-associated protein-4 inhibitors): results of a retrospective study. J. Clin. Med. Res. 11:4225–36
    [Google Scholar]
  116. 116. 
    Chae YK, Chiec L, Mohindra N, Gentzler R, Patel J, Giles F 2017. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunol. Immunother. 66:125–32
    [Google Scholar]
  117. 117. 
    Das S, Johnson DB. 2019. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J. Immunother. Cancer 7:1306
    [Google Scholar]
  118. 118. 
    Postow MA, Sidlow R, Hellmann MD 2018. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378:2158–68
    [Google Scholar]
  119. 119. 
    Buchbinder EI, Desai A. 2016. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 39:198–106
    [Google Scholar]
  120. 120. 
    Horvat TZ, Adel NG, Dang T-O, Momtaz P, Postow MA et al. 2015. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J. Clin. Oncol. 33:283193–98
    [Google Scholar]
  121. 121. 
    Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D et al. 2017. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J. Clin. Oncol. 35:7785–92
    [Google Scholar]
  122. 122. 
    Esfahani K, Miller WH. 2017. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N. Engl. J. Med. 376:201989–91
    [Google Scholar]
  123. 123. 
    Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R et al. 2018. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 124:183706–14
    [Google Scholar]
  124. 124. 
    Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS 2016. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin. Cancer Res. 22:4886–94
    [Google Scholar]
  125. 125. 
    Teulings H-E, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB et al. 2015. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J. Clin. Oncol. 33:7773–81
    [Google Scholar]
  126. 126. 
    Hua C, Boussemart L, Mateus C, Routier E, Boutros C et al. 2016. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152:145–51
    [Google Scholar]
  127. 127. 
    Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M et al. 2015. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol 151:111206–12
    [Google Scholar]
  128. 128. 
    Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM et al. 2007. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin. Cancer Res. 13:22 Part 16681–88
    [Google Scholar]
  129. 129. 
    Weber JS, O'Day S, Urba W, Powderly J, Nichol G et al. 2008. Phase I/II study of ipilimumab for patients with metastatic melanoma. J. Clin. Oncol. 26:365950–56
    [Google Scholar]
  130. 130. 
    Grimaldi A, Simeone E, Festino L, Giannarelli D, Palla M et al. 2015. Correlation between immune-related adverse events and response to pembrolizumab in advanced melanoma patients. J. Immunother. Cancer 3:Suppl. 2P186
    [Google Scholar]
  131. 131. 
    Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D et al. 2017. Systemic immunity is required for effective cancer immunotherapy. Cell 168:3487–502.e15
    [Google Scholar]
  132. 132. 
    De Angulo G, Yuen C, Palla SL, Anderson PM, Zweidler-McKay PA 2008. Absolute lymphocyte count is a novel prognostic indicator in ALL and AML: implications for risk stratification and future studies. Cancer 112:2407–15
    [Google Scholar]
  133. 133. 
    Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caracò C et al. 2014. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol. Immunother. 63:7675–83
    [Google Scholar]
  134. 134. 
    Martens A, Wistuba-Hamprecht K, Geukes Foppen M, Yuan J, Postow MA et al. 2016. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin. Cancer Res. 22:122908–18
    [Google Scholar]
  135. 135. 
    Martens A, Wistuba-Hamprecht K, Yuan J, Postow MA, Wong P et al. 2016. Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab. Clin. Cancer Res. 22:194848–58
    [Google Scholar]
  136. 136. 
    Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A et al. 2005. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353:252654–66
    [Google Scholar]
  137. 137. 
    Subrahmanyam PB, Dong Z, Gusenleitner D, Giobbie-Hurder A, Severgnini M et al. 2018. Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients. J. Immunother. Cancer 6:118
    [Google Scholar]
  138. 138. 
    Felix J, Lambert J, Roelens M, Maubec E, Guermouche H et al. 2016. Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response. Oncoimmunology 5:71136045
    [Google Scholar]
  139. 139. 
    Pirozyan MR, McGuire HM, Emran AA, Tseng H-Y, Tiffen JC et al. 2020. Pretreatment innate cell populations and CD4 T cells in blood are associated with response to immune checkpoint blockade in melanoma patients. Front. Immunol. 11:372
    [Google Scholar]
  140. 140. 
    Ribas A, Shin DS, Zaretsky J, Frederiksen J, Cornish A et al. 2016. PD-1 blockade expands intratumoral memory T cells. Cancer Immunol. Res. 4:3194–203
    [Google Scholar]
  141. 141. 
    Gide TN, Quek C, Menzies AM, Tasker AT, Shang P et al. 2019. Distinct immune cell populations define response to anti-PD-1 monotherapy and anti-PD-1/anti-CTLA-4 combined therapy. Cancer Cell 35:2238–55.e6
    [Google Scholar]
  142. 142. 
    de Coaña YP, Wolodarski M, Poschke I, Yoshimoto Y, Yang Y et al. 2017. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 8:1321539–53
    [Google Scholar]
  143. 143. 
    Wistuba-Hamprecht K, Martens A, Heubach F, Romano E, Geukes Foppen M et al. 2017. Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients. Eur. J. Cancer 73:61–70
    [Google Scholar]
  144. 144. 
    Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG et al. 2018. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175:4998–1013.e20
    [Google Scholar]
  145. 145. 
    Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S et al. 2019. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50:1195–211.e10
    [Google Scholar]
  146. 146. 
    Daud AI, Loo K, Pauli ML, Sanchez-Rodriguez R, Sandoval PM et al. 2016. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J. Clin. Investig. 126:93447–52
    [Google Scholar]
  147. 147. 
    Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M et al. 2018. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24:7994–1004
    [Google Scholar]
  148. 148. 
    Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B et al. 2017. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:765260–65
    [Google Scholar]
  149. 149. 
    Kamphorst AO, Pillai RN, Yang S, Nasti TH, Akondy RS et al. 2017. Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1–targeted therapy in lung cancer patients. PNAS 114:194993–98
    [Google Scholar]
  150. 150. 
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM et al. 2014. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:7528568–71
    [Google Scholar]
  151. 151. 
    Kagamu H, Kitano S, Yamaguchi O, Yoshimura K, Horimoto K et al. 2020. CD4+ T-cell immunity in the peripheral blood correlates with response to anti-PD-1 therapy. Cancer Immunol. Res. 8:3334–44
    [Google Scholar]
  152. 152. 
    Zappasodi R, Budhu S, Hellmann MD, Postow MA, Senbabaoglu Y et al. 2018. Non-conventional inhibitory CD4+Foxp3PD-1hi T cells as a biomarker of immune checkpoint blockade activity. Cancer Cell 33:61017–32.e7 Erratum. 2018. Cancer Cell 34(4):691
    [Google Scholar]
  153. 153. 
    Balatoni T, Mohos A, Papp E, Sebestyén T, Liszkay G et al. 2018. Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy. Cancer Immunol. Immunother. 67:1141–51
    [Google Scholar]
  154. 154. 
    Woods DM, Ramakrishnan R, Laino AS, Berglund A, Walton K et al. 2018. Decreased suppression and increased phosphorylated STAT3 in regulatory T cells are associated with benefit from adjuvant PD-1 blockade in resected metastatic melanoma. Clin. Cancer Res. 24:246236–47
    [Google Scholar]
  155. 155. 
    Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG et al. 2008. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. PNAS 105:83005–10
    [Google Scholar]
  156. 156. 
    Liakou CI, Kamat A, Tang DN, Chen H, Sun J et al. 2008. CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. PNAS 105:3914987–92
    [Google Scholar]
  157. 157. 
    Roh W, Chen P-L, Reuben A, Spencer CN, Prieto PA et al. 2017. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci. Transl. Med. 9:379eaah3560
    [Google Scholar]
  158. 158. 
    Arakawa A, Vollmer S, Tietze J, Galinski A, Heppt MV et al. 2019. Clonality of CD4+ blood T cells predicts longer survival with CTLA4 or PD-1 checkpoint inhibition in advanced melanoma. Front. Immunol. 10:1336
    [Google Scholar]
  159. 159. 
    Postow MA, Manuel M, Wong P, Yuan J, Dong Z et al. 2015. Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma. J. Immunother. Cancer 3:23
    [Google Scholar]
  160. 160. 
    Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR et al. 2018. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378:211976–86
    [Google Scholar]
  161. 161. 
    Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ et al. 2017. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171:4934–49.e16
    [Google Scholar]
  162. 162. 
    Hopkins AC, Yarchoan M, Durham JN, Yusko EC, Rytlewski JA et al. 2018. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight 3:13e122092
    [Google Scholar]
  163. 163. 
    Cha E, Klinger M, Hou Y, Cummings C, Ribas A et al. 2014. Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci. Transl. Med. 6:238238ra70
    [Google Scholar]
  164. 164. 
    Yost KE, Satpathy AT, Wells DK, Qi Y, Wang C et al. 2019. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 25:81251–59
    [Google Scholar]
  165. 165. 
    Wu TD, Madireddi S, de Almeida PE, Banchereau R, Chen Y-JJ et al. 2020. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature 579:7798274–78
    [Google Scholar]
  166. 166. 
    Ostrand-Rosenberg S, Fenselau C. 2018. Myeloid-derived suppressor cells: immune-suppressive cells that impair antitumor immunity and are sculpted by their environment. J. Immunol. 200:2422–31
    [Google Scholar]
  167. 167. 
    Noy R, Pollard JW. 2014. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:149–61
    [Google Scholar]
  168. 168. 
    Neubert NJ, Schmittnaegel M, Bordry N, Nassiri S, Wald N et al. 2018. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci. Transl. Med. 10:436eaan3311
    [Google Scholar]
  169. 169. 
    Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N et al. 2014. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63:3247–57
    [Google Scholar]
  170. 170. 
    Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M et al. 2015. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin. Cancer Res. 21:245453–59
    [Google Scholar]
  171. 171. 
    Sade-Feldman M, Kanterman J, Klieger Y, Ish-Shalom E, Olga M et al. 2016. Clinical significance of circulating CD33+CD11b+HLA-DR myeloid cells in patients with stage IV melanoma treated with ipilimumab. Clin. Cancer Res. 22:235661–72
    [Google Scholar]
  172. 172. 
    Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M et al. 2017. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep 18:1248–62
    [Google Scholar]
  173. 173. 
    McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI et al. 2018. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24:6749–57
    [Google Scholar]
  174. 174. 
    Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ et al. 2018. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat. Med. 24:2144–53
    [Google Scholar]
  175. 175. 
    Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang N-AAS et al. 2017. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170:61120–33.e17
    [Google Scholar]
  176. 176. 
    Hollingsworth RE, Jansen K. 2019. Turning the corner on therapeutic cancer vaccines. NPJ Vaccines 4:17
    [Google Scholar]
  177. 177. 
    Majzner RG, Mackall CL. 2019. Clinical lessons learned from the first leg of the CAR T cell journey. Nat. Med. 25:91341–55
    [Google Scholar]
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