Resistance to PD1/PDL1 checkpoint inhibition

  • Jake S. O'Donnell
    Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia

    School of Medicine, The University of Queensland, Herston 4006, Queensland, Australia

    Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia
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  • Georgina V. Long
    Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, Australia
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  • Richard A. Scolyer
    Melanoma Institute Australia, The University of Sydney, and Royal Prince Alfred Hospital, Australia
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  • Michele W.L. Teng
    Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia
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  • Mark J. Smyth
    Corresponding author at: Level 9, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston 4006, Queensland, Australia.
    Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia

    School of Medicine, The University of Queensland, Herston 4006, Queensland, Australia
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Published:November 26, 2016DOI:


      • Resistance to anti-PD1 therapy affects up to ∼60% of patients treated.
      • Resistance can be primary or acquired.
      • Tumor intrinsic mechanisms limiting tumor-specific T cells promote resistance.
      • Logical therapeutic combinations might prevent or treat resistant tumors.


      For the first time in decades, patients with difficult-to-treat cancers such as advanced stage metastatic melanoma are being offered a glimpse of hope in the form of immunotherapies. By targeting factors that foster the development and maintenance of an immunosuppressive microenvironment within tumors, these therapies release the brakes on the host’s own immune system; allowing cure of disease. Indeed, phase III clinical trials have revealed that therapies such as ipilimumab and pembrolizumab which target the CTLA4 and PD-1 immune checkpoints, respectively, have raised the three-year survival of patients with melanoma to ∼70%, and overall survival (>5 years) to ∼30%. Despite this unprecedented efficacy, many patients fail to respond, and more concerning, some patients who demonstrate encouraging initial responses to immunotherapy, can acquire resistance over time. There is now an urgent need to identify mechanisms of resistance, to predict outcome and to identify targets for combination therapy. Here, with the aim of guiding future combination trials that target specific resistance mechanisms to immunotherapies, we have summarised and discussed the current understanding of mechanisms promoting resistance to anti-PD1/PDL1 therapies, and how combination strategies which target these pathways might yield better outcomes for patients.


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        • Smyth M.J.
        • et al.
        Combination cancer immunotherapies tailored to the tumor microenvironment.
        Nat Rev Clin Oncol. 2015;
        • Sharma P.
        • Allison J.P.
        The future of immune checkpoint therapy.
        Science. 2015; 348: 56-61
        • Topalian S.L.
        • et al.
        Safety, activity, and immune correlates of anti–PD-1 antibody in cancer.
        N Engl J Med. 2012; 366: 2443-2454
        • Restifo N.P.
        • Smyth M.J.
        • Snyder A.
        Acquired resistance to immunotherapy and future challenges.
        Nat Rev Cancer. 2016; 16: 121-126
        • Swaika A.
        • Hammond W.A.
        • Joseph R.W.
        Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy.
        Mol Immunol. 2015; 67: 4-17
        • Ribas A.
        Adaptive immune resistance: how cancer protects from immune attack.
        Cancer Discovery. 2015; 5: 915-919
        • Chen L.
        • Han X.
        Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future.
        J Clin Invest. 2015; 125: 3384-3391
        • Mittal D.
        • et al.
        New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape.
        Curr Opin Immunol. 2014; 27: 16-25
        • Pardoll D.M.
        The blockade of immune checkpoints in cancer immunotherapy.
        Nat Rev Cancer. 2012; 12: 252-264
        • Wherry E.J.
        T cell exhaustion.
        Nat Immunol. 2011; 12: 492-499
        • Marzec M.
        • et al.
        Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7–H1).
        Proc Natl Acad Sci USA. 2008; 105: 20852-20857
        • Parsa A.T.
        • et al.
        Loss of tumor suppressor PTEN function increases B7–H1 expression and immunoresistance in glioma.
        Nat Med. 2007; 13: 84-88
        • Mittendorf E.A.
        • et al.
        PD-L1 expression in triple-negative breast cancer.
        Cancer Immunol Res. 2014; 2: 361-370
        • Keir M.E.
        • et al.
        PD-1 and its ligands in tolerance and immunity.
        Annu Rev Immunol. 2008; 26: 677-704
        • Tumeh P.C.
        • et al.
        PD-1 blockade induces responses by inhibiting adaptive immune resistance.
        Nature. 2014; 515: 568-571
        • Restifo N.P.
        • Smyth M.J.
        • Snyder A.
        Acquired resistance to immunotherapy and future challenges.
        Nat Rev Cancer. 2016; 16: 121-126
        • Topalian S.L.
        • et al.
        Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
        N Engl J Med. 2012; 366: 2443-2454
        • Balch C.M.
        • et al.
        Final version of 2009 AJCC melanoma staging and classification.
        J Clin Oncol. 2009; 27: 6199-6206
        • Robert C.
        • et al.
        Nivolumab in previously untreated melanoma without BRAF mutation.
        N Engl J Med. 2015; 372: 320-330
        • Robert C.
        • et al.
        Pembrolizumab versus ipilimumab in advanced melanoma.
        N Engl J Med. 2015; 372: 2521-2532
      1. Schachter J, Ribas A, Long GV. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival analysis of KEYNOTE-006, in ASCO Meeting Abstracts, 2016, 34:9504.

        • Larkin J.
        • et al.
        Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
        N Engl J Med. 2015; 373: 23-34
      2. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067), in ASCO Meeting Abstracts, 2016 34:9505.

      3. Robert C, Ribas A, Hamid O, Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001, in ASCO Meeting Abstracts, 2016 34:9503.

        • Postow M.A.
        • et al.
        Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
        N Engl J Med. 2015; 372: 2006-2017
      4. Hodi F, Postow MA, Chesney JA, Overall survival in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity in a phase II trial (CheckMate 069), in ASCO Meeting Abstracts, 2016 34:9518.

        • Teng M.W.
        • et al.
        Classifying cancers based on T-cell infiltration and PD-L1.
        Cancer Res. 2015; 75: 2139-2145
        • Wang C.
        • et al.
        In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates.
        Cancer Immunol Res. 2014; 2: 846-856
        • Blackburn S.D.
        • et al.
        Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade.
        Proc Natl Acad Sci USA. 2008; 105: 15016-15021
        • Sjöblom T.
        • et al.
        The consensus coding sequences of human breast and colorectal cancers.
        Science. 2006; 314: 268-274
        • Alexandrov L.B.
        • et al.
        Signatures of mutational processes in human cancer.
        Nature. 2013; 500: 415-421
        • Schumacher T.N.
        • Schreiber R.D.
        Neoantigens in cancer immunotherapy.
        Science. 2015; 348: 69-74
        • Kreiter S.
        • et al.
        Mutant MHC class II epitopes drive therapeutic immune responses to cancer.
        Nature. 2015; 520: 692-696
        • Rizvi N.A.
        • et al.
        Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
        Science. 2015; 348: 124-128
        • Martin A.M.
        • et al.
        Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance.
        Prostate Cancer Prostatic Dis. 2015; 18: 325-332
        • Van Allen E.M.
        • et al.
        Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.
        Science. 2015; 350: 207-211
        • Dunn G.P.
        • Old L.J.
        • Schreiber R.D.
        The three Es of cancer immunoediting.
        Annu Rev Immunol. 2004; 22: 329-360
        • Korkolopoulou P.
        • et al.
        Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer.
        Br J Cancer. 1996; 73: 148-153
        • Zhao F.
        • et al.
        Melanoma lesions independently acquire T-cell resistance during metastatic latency.
        Cancer Res. 2016;
        • Shin D.
        • et al.
        Innate resistance of PD-1 blockade through loss of function mutations in JAK resulting in inability to express PD-L1 upon interferon exposure.
        J Immunol Ther Cancer. 2015; 3: 1-2
        • Zaretsky J.M.
        • et al.
        Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
        N Engl J Med. 2016; 375: 819-829
        • Merad M.
        • et al.
        The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting.
        Annu Rev Immunol. 2013; 31: 563-604
        • Smith-Garvin J.E.
        • Koretzky G.A.
        • Jordan M.S.
        T cell activation.
        Annu Rev Immunol. 2009; 27: 591-619
        • Spranger S.
        • Bao R.
        • Gajewski T.F.
        Melanoma-intrinsic [bgr]-catenin signalling prevents anti-tumor immunity.
        Nature. 2015; 523: 231-235
        • Sivan A.
        • et al.
        Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.
        Science. 2015; 350: 1084-1089
        • Vetizou M.
        • et al.
        Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.
        Science. 2015; 350: 1079-1084
        • Ellis L.M.
        • Hicklin D.J.
        VEGF-targeted therapy: mechanisms of anti-tumor activity.
        Nat Rev Cancer. 2008; 8: 579-591
        • Young M.R.
        • et al.
        Tumor-derived cytokines induce bone marrow suppressor cells that mediate immunosuppression through transforming growth factor beta.
        Cancer Immunol Immunother. 1992; 35: 14-18
        • Commeren D.L.
        • et al.
        Paradoxical effects of interleukin-10 on the maturation of murine myeloid dendritic cells.
        Immunology. 2003; 110: 188-196
        • Hammer G.E.
        • Ma A.
        Molecular control of steady-state dendritic cell maturation and immune homeostasis.
        Annu Rev Immunol. 2013; 31: 743-791
        • Harty J.T.
        • Tvinnereim A.R.
        • White D.W.
        CD8+ T cell effector mechanisms in resistance to infection.
        Annu Rev Immunol. 2000; 18: 275-308
        • Fridman W.H.
        • et al.
        The immune contexture in human tumors: impact on clinical outcome.
        Nat Rev Cancer. 2012; 12: 298-306
        • Galon J.
        • et al.
        Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.
        Science. 2006; 313: 1960-1964
        • Tumeh P.C.
        • et al.
        PD-1 blockade induces responses by inhibiting adaptive immune resistance.
        Nature. 2014; 515: 568-571
        • Curran M.A.
        • et al.
        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. 2010; 107: 4275-4280
        • Duraiswamy J.
        • et al.
        Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.
        Cancer Res. 2013; 73: 3591-3603
        • Highfill S.L.
        • et al.
        Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.
        Sci Transl Med. 2014; 6: 237ra67
        • Wenzel J.
        • et al.
        Type I interferon-associated recruitment of cytotoxic lymphocytes: a common mechanism in regressive melanocytic lesions.
        Am J Clin Pathol. 2005; 124: 37-48
        • Ngiow S.F.
        • et al.
        A threshold level of intratumor CD8+ T-cell PD1 expression dictates therapeutic response to anti-PD1.
        Cancer Res. 2015; 75: 3800-3811
        • Wei F.
        • et al.
        Strength of PD-1 signaling differentially affects T-cell effector functions.
        Proc Natl Acad Sci USA. 2013; 110: E2480-E2489
        • Sznol M.
        • Chen L.
        Antagonist antibodies to PD-1 and B7–H1 (PD-L1) in the treatment of advanced human cancer.
        Clin Cancer Res. 2013; 19: 1021-1034
        • Zajac A.J.
        • et al.
        Viral immune evasion due to persistence of activated T cells without effector function.
        J Exp Med. 1998; 188: 2205-2213
        • Thommen D.S.
        • et al.
        Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors.
        Cancer Immunol Res. 2015; 3: 1344-1355
        • Koyama S.
        • et al.
        Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.
        Nat Commun. 2016; : 7
        • Spranger S.
        • et al.
        Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.
        Sci Transl Med. 2013; 5: 200ra116
        • Holmgaard R.B.
        • et al.
        Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4.
        J Exp Med. 2013; 210: 1389-1402
        • Spranger S.
        • et al.
        Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment.
        J Immunol Ther Cancer. 2014; 2: 3
        • Young A.
        • et al.
        Targeting cancer-derived adenosine: new therapeutic approaches.
        Cancer Discovery. 2014; 4: 879-888
        • Zhang B.
        CD73 promotes tumor growth and metastasis.
        Oncoimmunology. 2012; 1: 67-70
        • Gao Z.W.
        • Dong K.
        • Zhang H.Z.
        The roles of CD73 in cancer.
        Biomed Res Int. 2014; 2014: 460654
        • Allard B.
        • et al.
        Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs.
        Clin Cancer Res. 2013; 19: 5626-5635
        • Woodland D.L.
        • Kohlmeier J.E.
        Migration, maintenance and recall of memory T cells in peripheral tissues.
        Nat Rev Immunol. 2009; 9: 153-161
        • Harty J.T.
        • Badovinac V.P.
        Shaping and reshaping CD8+ T-cell memory.
        Nat Rev Immunol. 2008; 8: 107-119
        • Mueller S.N.
        • Mackay L.K.
        Tissue-resident memory T cells: local specialists in immune defence.
        Nat Rev Immunol. 2016; 16: 79-89
        • Farber D.L.
        • Yudanin N.A.
        • Restifo N.P.
        Human memory T cells: generation, compartmentalization and homeostasis.
        Nat Rev Immunol. 2014; 14: 24-35
        • Sallusto F.
        • Geginat J.
        • Lanzavecchia A.
        Central memory and effector memory T cell subsets: function, generation, and maintenance.
        Annu Rev Immunol. 2004; 22: 745-763
        • Mueller S.N.
        • et al.
        Memory T cell subsets, migration patterns, and tissue residence.
        Annu Rev Immunol. 2013; 31: 137-161
        • Wherry E.J.
        • Kurachi M.
        Molecular and cellular insights into T cell exhaustion.
        Nat Rev Immunol. 2015; 15: 486-499
        • Shin H.
        • Wherry E.J.
        CD8 T cell dysfunction during chronic viral infection.
        Curr Opin Immunol. 2007; 19: 408-415
        • Ribas A.
        • et al.
        PD-1 blockade expands intratumoral memory T cells.
        Cancer Immunol Res. 2016; 4: 194-203
        • Wolchok J.D.
        • Saenger Y.
        The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation.
        Oncologist. 2008; 13: 2-9
        • Weber J.S.
        • Kahler K.C.
        • Hauschild A.
        Management of immune-related adverse events and kinetics of response with ipilimumab.
        J Clin Oncol. 2012; 30: 2691-2697
        • Wolchok J.D.
        • et al.
        Nivolumab plus ipilimumab in advanced melanoma.
        N Engl J Med. 2013; 369: 122-133
        • Bulliard Y.
        • et al.
        OX40 engagement depletes intratumoral Tregs via activating FcgammaRs, leading to antitumor efficacy.
        Immunol Cell Biol. 2014; 92: 475-480
        • Guo Z.
        • et al.
        PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer.
        PLoS One. 2014; 9: e89350
        • Kurtulus S.
        • et al.
        TIGIT predominantly regulates the immune response via regulatory T cells.
        J Clin Invest. 2015; 125: 4053-4062
        • Sakuishi K.
        • et al.
        Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
        J Exp Med. 2010; 207: 2187-2194
        • Chauvin J.M.
        • et al.
        TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients.
        J Clin Invest. 2015; 125: 2046-2058
        • Sharabi A.B.
        • et al.
        Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen.
        Cancer Immunol Res. 2015; 3: 345-355
        • Zeng 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: 343-349
        • Loi S.
        • et al.
        Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.
        J Clin Oncol. 2013; 31: 860-867
        • Rios-Doria J.
        • et al.
        Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models.
        Neoplasia. 2015; 17: 661-670
        • Pauken K.E.
        • Wherry E.J.
        Overcoming T cell exhaustion in infection and cancer.
        Trends in Immunology. 2015; 36: 265-276
        • Twyman-Saint Victor C.
        • et al.
        Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
        Nature. 2015; 520: 373-377
        • Emens L.A.
        Cancer vaccines: on the threshold of success.
        Expert Opin Emerg Drugs. 2008; 13: 295-308
        • Menzies A.M.
        • Long G.V.
        Systemic treatment for BRAF-mutant melanoma: where do we go next?.
        Lancet Oncology. 2014; 15: e371-e381
        • Mok S.
        • et al.
        Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.
        BMC Cancer. 2015; 15: 1-10
        • Kakavand H.
        • et al.
        PD-L1 expression and tumor-infiltrating lymphocytes define different subsets of MAPK inhibitor-treated melanoma patients.
        Am Assoc Cancer Res. 2015; 21: 3140-3148
      5. Ribas A, Hodi FS, Lawrence DP, Pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma: Phase 1 KEYNOTE-022 study, in ASCO Meeting Abstracts, 2016 34:3014.

        • Bald T.
        • et al.
        Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation.
        Cancer Discovery. 2014; 4: 674-687
        • Gabrilovich D.I.
        • et al.
        Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function.
        Clin Cancer Res. 1999; 5: 2963-2970
        • Sanchez-Paulete A.R.
        • et al.
        Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells.
        Cancer Discovery. 2016; 6: 71-79
        • Zippelius A.
        • et al.
        Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment.
        Cancer Immunol Res. 2015; 3: 236-244
        • Kohlhapp F.J.
        • Kaufman H.L.
        Molecular pathways: mechanism of action for talimogene laherparepvec, a new oncolytic virus immunotherapy.
        Clin Cancer Res. 2015;
        • Andtbacka R.H.
        • et al.
        Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.
        J Clin Oncol. 2015; 33: 2780-2788
        • Woller N.
        • et al.
        Viral infection of tumors overcomes resistance to pd-1-immunotherapy by broadening neoantigenome-directed T-cell responses.
        Mol Ther. 2015; 23: 1630-1640
      6. Long GV, Dummer R, Ribas A, et al., Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma., in ASCO Meeting Abstracts, 2016 34:9568.

        • Nguyen L.T.
        • Ohashi P.S.
        Clinical blockade of PD1 and LAG3 [mdash] potential mechanisms of action.
        Nat Rev Immunol. 2015; 15: 45-56
        • Hickey P.
        • Stacy M.
        Adenosine A2A antagonists in Parkinson’s disease: what’s next?.
        Curr Neurol Neurosci Rep. 2012; 12: 376-385
        • Maute R.L.
        • et al.
        Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.
        Proc Natl Acad Sci. 2015; 112: E6506-E6514