Resistance to Checkpoint Blockade Inhibitors and Immunomodulatory Drugs

  • Anthony N. AudinoEmail author
  • Mitchell S. Cairo
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 21)


Cancer therapy has evolved from surgery and radiation to multi-agent chemotherapy, and although we have seen decreased mortality and increased cure rates, most of this therapy has continued to focus on the tumor itself, and not on the tumor microenvironment. Various cells within the tumor microenvironment have been implicated in leading to resistance to immune therapy. Through a complex system of steps, T-cells become activated after presentation of a specific antigen. Because continuous T-cell activation can lead to lymphoproliferation and unwanted autoimmunity, the human T-cell immune system has evolved into a process of checks-and-balances, referred to as immune checkpoints, that allows for co-inhibitory receptors to inhibit T-cell activation. Through the use of check point inhibitors, we have seen patients with cancers refractory to multiple treatments have durable responses, and in some, long term remissions. Some of the most studied inhibitors include Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4), although more have been identified. As we continue to explore possible treatment options for cancer, we must also be diligent in preemptively investigating how and why some patients will become resistant to these treatments, and what, if any, actions can be taken to circumvent this resistance.


Checkpoint blockade inhibitors, PD-1, CTLA-4 Lymphoma Resistance 



Antigen Presenting Cells


Autologous Stem Cell Transplant


Brentuximab Vedotin


Cancer Associated Fibroblasts


Children’s Oncology Group


Cytotoxic T-Lymphocyte Associated Antigen-4


Food and Drug Administration


Hodgkin Lymphoma


Hematopoietic Stem Cells


Intracellular Activation Motifs


Inducible Costimulatory


Indoleamine 2, 3-Droxygenase


Immunoreceptor Tyrosine Based Activation Motifs


Lymphocyte Activation Gene 3


Myeloid Derived Suppressor Cells


Major Histocompatibility Complex


Major Histocompatibility Complex Class I


Major Histocompatibility Complex Class II


Non-small Cell Lung Cancer


Objective Response Rate


Overall Survival


Programmed Cell Death Protein 1


Programmed Cell Death Ligand 1


Programmed Cell Death Ligand 2


Progressive Free Survival




Tumor Associated Macrophages


T-Cell Receptors


T-cell Immunoglobulin Mucin 3


Regulatory T-cells



This work was supported in part from the Pediatric Cancer Research Foundation and St. Baldrick’s Foundation. The authors would like to thank Virginia Davenport, RN and Erin Morris, RN in their assistance in the preparation of this manuscript.

Disclosure of Conflict of Interest

No potential conflicts of interest were disclosed.


  1. 1.
    Yuan Y, Jiang YC, Sun CK, Chen QM. Role of the tumor microenvironment in tumor progression and the clinical applications (review). Oncol Rep. 2016;35(5):2499–515.CrossRefGoogle Scholar
  2. 2.
    Wang Q, Wu X. Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment. Int Immunopharmacol. 2017;46:210–9.CrossRefGoogle Scholar
  3. 3.
    Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74–80.CrossRefGoogle Scholar
  4. 4.
    Hui L, Chen Y. Tumor microenvironment: sanctuary of the devil. Cancer Lett. 2015;368(1):7–13.CrossRefGoogle Scholar
  5. 5.
    Vardhana S, Younes A. The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints. Haematologica. 2016;101(7):794–802.CrossRefGoogle Scholar
  6. 6.
    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23.CrossRefGoogle Scholar
  7. 7.
    Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.CrossRefGoogle Scholar
  8. 8.
    Orkin SH, Nathan DG. Nathan and Oski’s hematology of infancy and childhood, vol. xxvi. 7th ed. Philadelphia: Saunders/Elsevier; 2009. p. 1841.Google Scholar
  9. 9.
    Rothenberg EV, Taghon T. Molecular genetics of T cell development. Annu Rev Immunol. 2005;23:601–49.CrossRefGoogle Scholar
  10. 10.
    Grossi CE, Favre A, Giunta M, Corte G. T cell differentiation in the thymus. Cytotechnology. 1991;5(Suppl 1):113–6.CrossRefGoogle Scholar
  11. 11.
    Viret C, Janeway CA Jr. MHC and T cell development. Rev Immunogenet. 1999;1(1):91–104.PubMedGoogle Scholar
  12. 12.
    Veillette A, Bookman MA, Horak EM, Bolen JB. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988;55(2):301–8.CrossRefGoogle Scholar
  13. 13.
    Nel AE. T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J Allergy Clin Immun. 2002;109(5):758–70.CrossRefGoogle Scholar
  14. 14.
    Colombo MP, Piconese S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer. 2007;7(11):880–7.CrossRefGoogle Scholar
  15. 15.
    Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94(1):25–39.CrossRefGoogle Scholar
  16. 16.
    Hude I, Sasse S, Engert A, Brockelmann PJ. The emerging role of immune checkpoint inhibition in malignant lymphoma. Haematologica. 2017;102(1):30–42.CrossRefGoogle Scholar
  17. 17.
    Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member of the immunoglobulin superfamily—CTLA-4. Nature. 1987;328(6127):267–70.CrossRefGoogle Scholar
  18. 18.
    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6.CrossRefGoogle Scholar
  19. 19.
    Auchincloss H, Turka LA. CTLA-4: not all costimulation is stimulatory. J Immunol. 2011;187(7):3457–8.CrossRefGoogle Scholar
  20. 20.
    Menter T, Tzankov A. Mechanisms of immune evasion and immune modulation by lymphoma cells. Front Oncol. 2018;8:54.CrossRefGoogle Scholar
  21. 21.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.CrossRefGoogle Scholar
  22. 22.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.CrossRefGoogle Scholar
  23. 23.
    Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015;33(10):1191–6.CrossRefGoogle Scholar
  24. 24.
    Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366(26):2517–9.CrossRefGoogle Scholar
  25. 25.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.CrossRefGoogle Scholar
  26. 26.
    Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113(7):1581–8.CrossRefGoogle Scholar
  27. 27.
    Diefenbach CS, Hong FX, Cohen JB, Robertson MJ, Ambinder RF, Fenske TS, et al. Preliminary safety and efficacy of the combination of Brentuximab Vedotin and Ipilimumab in relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer research group (E4412). Blood. 2015;126:23.Google Scholar
  28. 28.
    Oiseth SJ, Aziz Mohamed S. Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat. 2017;3:250–61.CrossRefGoogle Scholar
  29. 29.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521–32.CrossRefGoogle Scholar
  30. 30.
    Ribas A, Wolchok JD, Robert C, Kefford R, Hamid O, Daud A, et al. Updated clinical efficacy of the anti-Pd-1 monoclonal antibody Pembrolizumab (Mk-3475) in 411 patients with Melanoma. Eur J Cancer. 2015;51:E24–E.CrossRefGoogle Scholar
  31. 31.
    Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.CrossRefGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    Goodman A, Patel SP, Kurzrock R. PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat Rev Clin Oncol. 2017;14(4):203–20.CrossRefGoogle Scholar
  34. 34.
    Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J, et al. Programmed death-1 blockade with Pembrolizumab in patients with classical Hodgkin lymphoma after Brentuximab Vedotin failure. J Clin Oncol. 2016;34(31):3733–9.CrossRefGoogle Scholar
  35. 35.
    Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42.CrossRefGoogle Scholar
  36. 36.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.CrossRefGoogle Scholar
  37. 37.
    Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol. 2018;36(14):1428–39.CrossRefGoogle Scholar
  38. 38. Risk-based, Response-adapted, Phase II Open-label Trial of Nivolumab + Brentuximab Vedotin (N + Bv) for Children, Adolescents, and Young Adults With Relapsed/Refractory (R/R) CD30 + Classic Hodgkin Lymphoma (cHL) After Failure of First-line Therapy, Followed by Brentuximab + Bendamustine (Bv + B) for Participants With a Suboptimal Response (CheckMate 744: CHECKpoint Pathway and Nivolumab Clinical Trial Evaluation) [cited 2018 October 7, 2016]. Available from:
  39. 39.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.CrossRefGoogle Scholar
  40. 40.
    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. New Engl J Med. 2017;377(14):1345–56.CrossRefGoogle Scholar
  41. 41.
    Michot JM, Lazarovici J, Ghez D, Danu A, Ferme C, Bigorgne A, et al. Challenges and perspectives in the immunotherapy of Hodgkin lymphoma. Eur J Cancer. 2017;85:67–77.CrossRefGoogle Scholar
  42. 42.
    Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34(23):2690–7.CrossRefGoogle Scholar
  43. 43.
    Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.CrossRefGoogle Scholar
  44. 44.
    Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–65.CrossRefGoogle Scholar
  45. 45.
    Heigener DF, Reck M. Advanced non-small cell lung cancer: the role of PD-L1 inhibitors. J Thorac Dis. 2018;10(Suppl 13):S1468–S73.CrossRefGoogle Scholar
  46. 46.
    Shirley M. Avelumab: a review in metastatic Merkel cell carcinoma. Target Oncol. 2018;13(3):409–16.CrossRefGoogle Scholar
  47. 47.
    O’Donnell JS, Long GV, Scolyer RA, Teng MW, Smyth MJ. Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev. 2017;52:71–81.CrossRefGoogle Scholar
  48. 48.
    O’Donnell JS, Smyth MJ, Teng MW. Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade? Genome Med. 2016;8(1):111.CrossRefGoogle Scholar
  49. 49.
    Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819–29.CrossRefGoogle Scholar
  50. 50.
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.CrossRefGoogle Scholar
  51. 51.
    Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 2015;75(11):2139–45.CrossRefGoogle Scholar
  52. 52.
    Tang H, Wang Y, Chlewicki LK, Zhang Y, Guo J, Liang W, et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell. 2016;29(3):285–96.CrossRefGoogle Scholar
  53. 53.
    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.CrossRefGoogle Scholar
  54. 54.
    Bai J, Gao Z, Li X, Dong L, Han W, Nie J. Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget. 2017;8(66):110693–707.CrossRefGoogle Scholar
  55. 55.
    Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.CrossRefGoogle Scholar
  56. 56.
    Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118(1):9–16.CrossRefGoogle Scholar
  57. 57.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.CrossRefGoogle Scholar
  58. 58.
    Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, et al. Evolution of Neoantigen landscape during immune checkpoint blockade in non-small cell lung Cancer. Cancer Discov. 2017;7(3):264–76.CrossRefGoogle Scholar
  59. 59.
    Li L, Dong M, Wang XG. The implication and significance of Beta 2 microglobulin: a conservative multifunctional regulator. Chin Med J. 2016;129(4):448–55.CrossRefGoogle Scholar
  60. 60.
    Roemer MG, Advani RH, Redd RA, Pinkus GS, Natkunam Y, Ligon AH, et al. Classical Hodgkin lymphoma with reduced beta2M/MHC class I expression is associated with inferior outcome independent of 9p24.1 status. Cancer Immunol Res. 2016;4(11):910–6.CrossRefGoogle Scholar
  61. 61.
    Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci USA. 2013;110(27):11091–6.CrossRefGoogle Scholar
  62. 62.
    Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, Loi S, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res. 2015;3(5):506–17.CrossRefGoogle Scholar
  63. 63.
    Ribas A. Releasing the brakes on Cancer immunotherapy. N Engl J Med. 2015;373(16):1490–2.CrossRefGoogle Scholar
  64. 64.
    Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39.CrossRefGoogle Scholar
  65. 65.
    Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pediatric Hematology/Oncology/BMT, Nationwide Children’s HospitalThe Ohio State UniversityColumbusUSA
  2. 2.Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and AnatomyNew York Medical CollegeValhallaUSA

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