Document Type : Review Article


1 Faculty of Medicine and Pharmacy of Casablanca, University of Hassan 2, Casablanca, Morocco

2 Neuropsychology Department, University of Paris 8, Vincennes-Saint-Denis, Paris, France


The aim of this research is to use bibliometric analysis to investigate the status and patterns of the 100 most frequently cited publications regarding the cytotoxic Tlymphocyte- associated protein (CTLA-4) research for cancer. The articles published on the topic were retrieved from the core collection database of Web of Science and PubMed using the Medical Subject Heading (MeSH) of “CTLA-4” from 1986 to December 6, 2020. The selected articles were examined and the bibliometric data compiled based on the number of citations, the author’s name, journal, publication year, institution, country, and co-occurrence keywords. 4,874 eligible papers were returned from the Web of Science Core Collection Database and PubMed. The citation frequency ranged from 2372 to 205, with a median of 460, and the top cited paper had 2372 citations. The journals with the most papers were Cell (n = 8, 3541 citations, Impact Factor (IF) = 41.577) and Journal of Experimental Medicine (n = 7, 2716 citations, IF = 10.790). Most of the published papers were from the United States of America (USA) (41.8%). A total of 485 institutes and 29 countries were involved in these 100 articles. There were 1192 authors and the author with the highest number of papers was the Nobel Prize winner, Professor James P. Allison (17 papers; 8700 citations). CTLA-4 blockade was the most frequent keyword (42.1%), followed by metastatic melanoma (4.26%). This work presents an important bibliographic source and can be saved as a reference for future medical health research on the function of CTLA-4 in cancer immunotherapy.


How to cite this article:

Hilal El Idrissi H, Balar I. Top 100 most cited publications on CTLA-4 molecule in cancer research: A bibliometric analysis. Middle East J Cancer. 2023;14(1):1-16. doi:10.30476/ mejc.2022.90280.1568.

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi: 10.3322/caac.21660.
  2. Ichim CV. Revisiting immunosurveillance and immunostimulation: Implications for cancer immunotherapy. J Transl Med. 2005;3(1):8. doi: 10.1186/1479-5876-3-8.
  3. Burnet M. Cancer; a biological approach. I. The processes of control. Br Med J. 1957;1(5022):779- 86. doi: 10.1136/bmj.1.5022.779.
  4. Zang X. 2018 Nobel Prize in medicine awarded to cancer immunotherapy: Immune checkpoint blockade - A personal account. Genes Dis. 2018;5(4):302-3. doi: 10.1016/j.gendis.2018.10.003.
  5. Huang PW, Chang JW. Immune checkpoint inhibitors win the 2018 Nobel Prize. Biomed J. 2019;42(5):299- 306. doi: 10.1016/
  6. Ling V, Wu PW, Finnerty HF, Agostino MJ, Graham JR, Chen S, et al. Assembly and annotation of human chromosome 2q33 sequence containing the CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, and microarray approaches. Genomics. 2001;78(3):155-68. doi: 10.1006/geno.2001.6655.
  7. Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity. 1996;4(6):535-43. doi: 10.1016/s1074-7613(00)80480-x.
  8. Olive D, le Thi S, Xerri L, Hirsch I, Nunès JA. The role of co-inhibitory signals driven by CTLA-4 in immune system. [Article in French] Med Sci (Paris). 2011;27(10):842-9. doi: 10.1051/medsci/20112710012.
  9. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995 1;182(2):459-65. doi: 10.1084/jem.182.2.459.
  10. Mansh M. Ipilimumab and cancer immunotherapy: a new hope for advanced stage melanoma. Yale J Biol Med. 2011;84(4):381-9.
  11. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017; 377(14):1345-56. doi: 10.1056/NEJMoa1709684.
  12. MeSH Databases. [Internet] NCBI Home MeSH (2020). [cited on: 06 December 2020]. Available from:
  13. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009.21;6(7):e1000097. doi: 10.1371/journal.pmed. 1000097.
  14. Journal Citation Reports. [Internet] Clarivate Analytics (2018). [cited on: 27 June 2018]. Available from:
  15. Garfield E, Paris SW, Stock WG. HistCiteTM: A software tool for informetric analysis of citation linkage. Informatrics. 2006;57(8):391-400.
  16. Van Eck NJ, Waltman L. Software survey: VOSviewer, a computer program for bibliometric mapping. Scientometrics. 2010;84(2):523-38. doi: 10.1007/ s11192-009-0146-3.
  17. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;11;369(2):122-33. doi: 10.1056/NEJMoa1 302369.
  18. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015.10;33(17):1974-82. doi: 10.1200/JCO.2014. 59.4358.
  19. Petrelli F, De Stefani A, Trevisan F, Parati C, Inno A, Merelli B, et al. Combination of radiotherapy and immunotherapy for brain metastases: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2019;144:102830. doi: 10.1016/j.critrevonc. 2019.102830.
  20. Kotlowska MP, Rueda AG, Olmedo ME, Benito A, Roldán AS, Fernandez Méndez MA, et al. Efficacy of immunotherapy in sarcomatoid lung cancer, a case report and literature review. Respir Med Case Rep. 2019;26:310-4. doi: 10.1016/j.rmcr.2019.02.017.
  21. Bates JE, Morris CG, Milano MT, Yeung AR, Hoppe BS. Immunotherapy with hypofractionated radiotherapy in metastatic non-small cell lung cancer: An analysis of the National Cancer Database. Radiother Oncol. 2019;138:75-9. doi: 10.1016/j.radonc. 2019.06.004.
  22. Esteva FJ, Hubbard-Lucey VM, Tang J, Pusztai L. Immunotherapy and targeted therapy combinations in metastatic breast cancer. Lancet Oncol. 2019;20(3): e175–86.doi: 10.1016/S1470-2045(19)30026-9.
  23. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-33. doi: 10.1056/NEJMoa1302369. Erratum in: N Engl J Med. 2018;379(22):2185.
  24. Gao Y, Shi S, Ma W, Chen J, Cai Y, Ge L, et al. Bibliometric analysis of global research on PD-1 and PD-L1 in the field of cancer. Int Immunopharmacol. 2019;72:374-84. doi: 10.1016/j.intimp.2019.03.045.
  25. Zhao X, He L, Mao K, Chen D, Jiang H, Liu Z. The research status of immune checkpoint blockade by anti-CTLA4 and anti-PD1/PD-l1 antibodies in tumor immunotherapy in China: A bibliometrics study. Medicine (Baltimore). 2018;97(15):e0276. doi: 10.1097/MD.0000000000010276.
  26. Zhong Q, Li BH, Zhu QQ, Zhang ZM, Zou ZH, Jin YH. The top 100 highly cited original articles on immunotherapy for childhood leukemia. Front Pharmacol. 2019;10:1100. doi:10.3389/fphar. 2019.01100.
  27. Baş Y, Şenel E. A Holistic evaluation of articles on PD-1 and PD-L1 published between 1975 and 2017: A bibliometric analysis. Cancer Inform. 2019;18:1– 8. doi:10.1177/1176935119852620.
  28. Gilman NV. Analysis for science librarians of the 2018 nobel prize in physiology or medicine: The life and work of James P. Allison and Tasuku Honjo. Sci Technol Libr. 2019;38(1):1-29. doi: 10.1080/0194262X. 2018.1558165.
  29. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64. doi: 10.1038/nrc3239.
  30. World economic situation and prospects 2020. [Internet] Department of Economic and Social Affairs of United Nations. [cited on: 06 December 2020].Available from: development/desa/dpad/publication/world-economicsituation- and-prospects-2020/
  31. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73(12):3591- 603. doi: 10.1158/0008-5472.CAN-12-4100.
  32. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189-99. doi: 10.1056/ NEJMoa1406498. Erratum in: N Engl J Med. 2018; 379(22):2185.
  33. Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1(1):32-42. doi: 10.1158/2326- 6066.
  34. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015,3;348(6230):56-61. doi: 10.1126/science.aaa8172.
  35. O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter singlearm phase II study. Ann Oncol. 2010;21(8):1712-7. doi: 10.1093/annonc/mdq013.
  36. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015.13;27(4):450- 61. doi: 10.1016/j.ccell.2015.03.001.
  37. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202-16. doi: 10.1158/2159-8290.
  38. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-84. doi: 10.1016/S1470- 2045(15)70076-8.
  39. Chen Q, Xu L, Liang C, Wang C, Peng R, Liu Z. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat Commun. 2016;7:13193. doi: 10.1038/ncomms13193.
  40. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-31. doi: 10.1056/ NEJMoa1 112824.
  41. Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11(11):805-12. doi: 10.1038/nrc3153.
  42. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castrationresistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24(7):1813-21. doi: 10.1093/annonc/mdt107.
  43. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80. doi: 10.1073/pnas. 0915174107.
  44. Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011;16(1):5-24. doi: 10.1634/ theoncologist.2010-0190.
  45. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463- 9. doi: 10.1126/science.aaf1490.
  46. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24(1):75-83. doi: 10.1093/annonc/ mds213.
  47. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207-11. doi: 10.1126/science.aad0095.
  48. Cancer Genome Atlas Research Network. Electronic address:; Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017;169(7):1327-41.e23. doi: 10.1016/j.cell.2017.05.046.
  49. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577-81. doi: 10.1038/nature13988.
  50. Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116(7):1767-75. doi: 10.1002/cncr.24951.
  51. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537-44. doi: 10.1182/blood-2008-12-195792.
  52. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014;6(226):226ra32. doi: 10.1126/ scitranslmed.3008095.
  53. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205-14. doi: 10.1016/j.cell.2015.03.030.
  54. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27(1):109-18. doi: 10.1038/cr.2016.151.
  55. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-84. doi: 10.1126/science. aad1329.
  56. Melero I, Berman DM, Aznar MA, Korman AJ, Pérez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457-72. doi: 10.1038/nrc3973.
  57. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-7. doi: 10.1200/JCO.2012.41.6750.
  58. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13(5):273-90. doi: 10.1038/nrclinonc.2016.25.
  59. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231-5. doi: 10.1038/ nature14404.
  60. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210(7):1389-402. doi: 10.1084/jem.20130066.
  61. Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275-87. doi: 10.1038/nrc.2016.36.
  62. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J,et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi: 10.1093/annonc/ mdx225.
  63. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379-88. doi: 10.1158/1078-0432.CCR-09-0265.
  64. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17(12):e542- e551. doi: 10.1016/S1470-2045(16)30406-5.
  65. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321-30. doi: 10.1038/nature21349.
  66. Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13(3):143-58. doi: 10.1038/nrclinonc.2015.209.
  67. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046-54. doi: 10.1200/JCO.2011.38.4032.
  68. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73. doi: 10.1186/s12916-016- 0623-5.
  69. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165(1):35-44. doi: 10.1016/j.cell.2016.02.065.
  70. BCarthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16(10):2861-71. doi: 10.1158/1078-0432.CCR- 10-0569.
  71. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707-23. doi: 10.1016/j.cell.2017.01.017.
  72. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375(18):1767-78. doi: 10.1056/NEJMra1514296.
  73. Tirosh I, Izar B, Prakadan SM, Wadsworth MH 2nd, Treacy D, Trombetta JJ, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352(6282):189- 96. doi: 10.1126/science.aad0501.
  74. J Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell. 2016;167(2):397-404.e9. doi: 10.1016/j.cell.2016. 08.069.
  75. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castrationresistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700-12. doi: 10.1016/S1470- 2045(14)70189-5.
  76. Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, et al. Safety profiles of anti-CTLA- 4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473-86. doi: 10.1038/nrclinonc.2016.58.
  77. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013;210(9):1695-710. doi: 10.1084/jem.20130579.
  78. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36(7):382-9. doi: 10.1097/CJI.0b013e31829fb7a2.
  79. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162(6):1229-41. doi: 10.1016/j.cell. 2015.08.016.
  80. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559-74. doi: 10.1093/annonc/mdv623.
  81. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917-27. doi: 10.1158/0008-5472.CAN-11-1620.
  82. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692. doi: 10.1038/ncomms7692.
  83. Myers G. Immune-related adverse events of immune checkpoint inhibitors: a brief review. Curr Oncol. 2018;25(5):342-7. doi:10.3747/co.25.4235.
  84. Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011;71(10):3540- 51. doi: 10.1158/0008-5472.CAN-11-0096.
  85. Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et al. Activation of the PD-1 pathway contributes to immune escape in EGFRdriven lung tumors. Cancer Discov. 2013;3(12): 1355-63. doi: 10.1158/2159-8290.CD-13-0310.
  86. Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD. Immune modulation in cancer with antibodies. Annu Rev Med. 2014;65:185-202. doi: 10.1146/annurev-med-092012-112807.
  87. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5(1):43-51. doi: 10.1158/2159- 8290.CD-14-0863.
  88. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923-37. doi: 10.1016/ j.ccell.2014.10.018.
  89. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8):1717-25. doi: 10.1084/jem. 20082492.
  90. Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013;210(9):1685-93. doi: 10.1084/jem.20130573.
  91. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781-90. doi: 10.1084/jem.20131916.
  92. Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med. 2013;5(215):215ra172. doi: 10.1126/scitranslmed.3006597.
  93. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAPexpressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 2013;110(50):20212-7. doi: 10.1073/pnas.1320318110.
  94. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27(1):109-18. doi: 10.1038/cr.2016.151.
  95. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350- 5. doi: 10.1126/science.aar4060
  96. Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853- 62. doi: 10.1016/S0140-6736(17)31601-X.
  97. Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547(7662):222-6. doi: 10.1038/nature23003.
  98. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA- 4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8(1):e53745. doi: 10.1371/journal.pone.0053745.
  99. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Set al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828-33. doi: 10.1097/CJI.0b013e3181 eec14c.
  100. Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015;13:211. doi: 10.1186/s12916-015-0455-8.
  101. Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. doi: 10.1186/s13073-017-0424-2.
  102. Palucka AK, Coussens LM. The basis of oncoimmunology. Cell. 2016;164(6):1233-47. doi: 10.1016/j.cell.2016.01.049.
  103. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015;125(9):3384-91. doi: 10.1172/JCI80011.
  104. Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov. 2016;6(8):827-37. doi: 10.1158/2159-8290.
  105. Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med. 2010;207(3):637-50. doi: 10.1084/jem.20091918.
  106. Madan RA, Mohebtash M, Arlen PM, Vergati M, Rauckhorst M, Steinberg SM, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(5):501-8. doi: 10.1016/S1470- 2045(12)70006-2.
  107. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98- 106. doi: 10.1097/COC.0000000000000239.
  108. van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar RJ, van der Sluis TM, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factortransduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castrationresistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(5):509-17. doi: 10.1016/S1470-2045(12)70007-4.
  109. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61(7):1019-31. doi: 10.1007/s00262-011-1172- 6.
  110. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212(2):139-48. doi: 10.1084/jem.20140559.
  111. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14(12):1212-8. doi: 10.1038/ni.2762.
  112. Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561. doi: 10.3389/fphar.2017.00561.
  113. Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343-9. doi: 10.1016/j.ijrobp.2012.12.025.
  114. Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20(20):5290-301. doi: 10.1158/1078-0432.CCR-14-0514.
  115. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1(6):365- 72. doi: 10.1158/2326-6066.CIR-13-0115.
  116. Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci USA. 2015;112(19):6140-5. doi: 10.1073/pnas.1417320112.
  117. Postow MA, Sidlow R, Hellmann MD. Immunerelated adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158- 68. doi: 10.1056/NEJMra1703481.
  118. Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS; MDX010-20 Investigators. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675-82. doi: 10.1002/cncr.27969.
  119. Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, et al. A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591-8. doi: 10.1158/1078- 0432.CCR-09-1024.
  120. Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther. 2015;37(4):764- 82. doi: 10.1016/j.clinthera.2015.02.018.
  121. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PDL1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19(19):5300-9. doi: 10.1158/1078-0432.
  122. Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A. 2014;111(32):11774-9. doi: 10.1073/ pnas.1410626111.
  123. Cantwell-Dorris ER, O'Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10(3):385- 94. doi: 10.1158/1535-7163.
  124. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017;18(1):248-62. doi: 10.1016/j.celrep.2016.12.01.
  125. Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81-8. doi: 10.1016/j.jhep.2013.02.022.
  126. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: A review. JAMA Oncol. 2016;2(10):1346-53. doi: 10.1001/ jamaoncol.2016.1051.
  127. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18(7):2039-47. doi: 10.1158/1078-0432.CCR- 11-1823.
  128. Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NAS, Andrews MC, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017;170(6):1120-33.e17. doi: 10.1016/j.cell.2017.07.024.