Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma
Tóm tắt
Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFNγ in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with αPD-1 mAbs, with or without αCTLA-4 mAbs, failed in well-established tumors, recapitulating clinical results. Agonist αCD40 mAbs with chemotherapy induced T-cell immunity and reversed the complete resistance of pancreatic tumors to αPD-1 and αCTLA-4. The combination of αCD40/chemotherapy plus αPD-1 and/or αCTLA-4 induced regression of subcutaneous tumors, improved overall survival, and conferred curative protection from multiple tumor rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers, although no cures were observed. Our findings suggest that in pancreatic carcinoma, a nonimmunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T-cell response with αCD40/chemotherapy. Cancer Immunol Res; 3(4); 399–411. ©2015 AACR.
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Rahib, 2014, Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States, Cancer Res, 74, 2913, 10.1158/0008-5472.CAN-14-0155
Conroy, 2011, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N Engl J Med, 364, 1817, 10.1056/NEJMoa1011923
Hoff von, 2013, Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N Engl J Med, 369, 1691, 10.1056/NEJMoa1304369
Schreiber, 2011, Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion, Science, 331, 1565, 10.1126/science.1203486
Odorizzi, 2012, Inhibitory receptors on lymphocytes: insights from infections, J Immunol, 188, 2957, 10.4049/jimmunol.1100038
Sznol, 2013, Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer, Clin Cancer Res, 19, 1021, 10.1158/1078-0432.CCR-12-2063
Page, 2014, Immune modulation in cancer with antibodies, Annu Rev Med, 65, 185, 10.1146/annurev-med-092012-112807
Pardoll, 2012, The blockade of immune checkpoints in cancer immunotherapy, Nat Rev Cancer, 12, 252, 10.1038/nrc3239
Powles, 2014, MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer, Nature, 515, 558, 10.1038/nature13904
Herbst, 2014, Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients, Nature, 515, 563, 10.1038/nature14011
Hodi, 2010, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, 363, 711, 10.1056/NEJMoa1003466
Brahmer, 2012, Safety and activity of anti-PD-L1 antibody in patients with advanced cancer, N Engl J Med, 366, 2455, 10.1056/NEJMoa1200694
Topalian, 2012, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer, N Engl J Med, 366, 2443, 10.1056/NEJMoa1200690
Hamid, 2013, Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma, N Engl J Med, 369, 134, 10.1056/NEJMoa1305133
Blackburn, 2009, Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection, Nat Immunol, 10, 29, 10.1038/ni.1679
Crawford, 2014, Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection, Immunity, 40, 289, 10.1016/j.immuni.2014.01.005
Nishimura, 2001, Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice, Science, 291, 319, 10.1126/science.291.5502.319
Keir, 2008, PD-1 and its ligands in tolerance and immunity, Annu Rev Immunol, 26, 677, 10.1146/annurev.immunol.26.021607.090331
Curiel, 2003, Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity, Nat Med, 9, 562, 10.1038/nm863
Dong, 2002, Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion, Nat Med, 8, 793, 10.1038/nm730
Duraiswamy, 2013, Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors, Cancer Res, 73, 3591, 10.1158/0008-5472.CAN-12-4100
Tivol, 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, 541, 10.1016/1074-7613(95)90125-6
Peggs, 2009, 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, 206, 1717, 10.1084/jem.20082492
Simpson, 2013, Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma, J Exp Med, 210, 1695, 10.1084/jem.20130579
Selby, 2013, Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells, Cancer Immunol Res, 1, 32, 10.1158/2326-6066.CIR-13-0013
Kvistborg, 2014, Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response, Sci Transl Med, 6, 254ra128, 10.1126/scitranslmed.3008918
Zamarin, 2014, Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy, Sci Transl Med, 6, 226ra32, 10.1126/scitranslmed.3008095
Gajewski, 2010, Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy, Cancer J, 16, 399, 10.1097/PPO.0b013e3181eacbd8
Ji, 2011, An immune-active tumor microenvironment favors clinical response to ipilimumab, Cancer Immunol Immunother, 61, 1019, 10.1007/s00262-011-1172-6
Royal, 2010, Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma, J Immunother, 33, 828, 10.1097/CJI.0b013e3181eec14c
Le, 2013, Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer, J Immunother, 36, 382, 10.1097/CJI.0b013e31829fb7a2
Wolchok, 2013, Nivolumab plus ipilimumab in advanced melanoma, N Engl J Med, 369, 122, 10.1056/NEJMoa1302369
Taube, 2012, Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape, Sci Transl Med, 4, 127ra37, 10.1126/scitranslmed.3003689
Taube, 2014, Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy, Clin Can Res, 20, 5064, 10.1158/1078-0432.CCR-13-3271
Lyford-Pike, 2013, Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma, Cancer Res, 73, 1733, 10.1158/0008-5472.CAN-12-2384
Spranger, 2013, Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells, Sci Transl Med, 5, 200ra116, 10.1126/scitranslmed.3006504
Bald, 2014, Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation, Cancer Discov, 4, 674, 10.1158/2159-8290.CD-13-0458
Zhou, 2010, Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization, J Immunol, 185, 5082, 10.4049/jimmunol.1001821
Hingorani, 2005, Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice, Cancer Cell, 7, 469, 10.1016/j.ccr.2005.04.023
Clark, 2007, Dynamics of the immune reaction to pancreatic cancer from inception to invasion, Cancer Res, 67, 9518, 10.1158/0008-5472.CAN-07-0175
Clark, 2008, Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer, Cancer Lett, 279, 1, 10.1016/j.canlet.2008.09.037
Beatty, 2011, CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans, Science, 331, 1612, 10.1126/science.1198443
Bayne, 2012, Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer, Cancer Cell, 21, 822, 10.1016/j.ccr.2012.04.025
Elgueta, 2009, Molecular mechanism and function of CD40/CD40L engagement in the immune system, Immunol Rev, 229, 152, 10.1111/j.1600-065X.2009.00782.x
Nowak, 2003, Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors, Cancer Res, 63, 4490
Rhim, 2012, EMT and dissemination precede pancreatic tumor formation, Cell, 148, 349, 10.1016/j.cell.2011.11.025
Paley, 2012, Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection, Science, 338, 1220, 10.1126/science.1229620
Doering, 2012, Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory, Immunity, 37, 1130, 10.1016/j.immuni.2012.08.021
Wherry, 2007, Molecular signature of CD8+ T cell exhaustion during chronic viral infection, Immunity, 27, 670, 10.1016/j.immuni.2007.09.006
Barber, 2006, Restoring function in exhausted CD8 T cells during chronic viral infection, Nature, 439, 682, 10.1038/nature04444
Blackburn, 2008, Selective expansion of a subset of exhausted CD8 T cells by PD-L1 blockade, Proc Natl Acad Sci U S A, 105, 15016, 10.1073/pnas.0801497105
Galon, 2013, The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures, Immunity, 39, 11, 10.1016/j.immuni.2013.07.008
Cho, 2009, Optimized peptide vaccines eliciting extensive CD8 T-cell responses with therapeutic antitumor effects, Cancer Res, 69, 9012, 10.1158/0008-5472.CAN-09-2019
Buhtoiarov, 2010, Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages, Immunology, 132, 226, 10.1111/j.1365-2567.2010.03357.x
Vonderheide, 2013, CD40 immunotherapy for pancreatic cancer, Cancer Immunol Immunother, 62, 949, 10.1007/s00262-013-1427-5
Shepard, 2012, Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer, Gut, 62, 112
Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell, 21, 418, 10.1016/j.ccr.2012.01.007
Rhim, 2014, Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma, Cancer Cell, 25, 735, 10.1016/j.ccr.2014.04.021
Vonderheide, 2013, Inflammatory networks and immune surveillance of pancreatic carcinoma, Curr Opin Immunol, 25, 200, 10.1016/j.coi.2013.01.006
Hiraoka, 2006, Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions, Clin Can Res, 12, 5423, 10.1158/1078-0432.CCR-06-0369
De Monte, 2011, Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer, J Exp Med, 208, 469, 10.1084/jem.20101876
Fukunaga, 2004, CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma, Pancreas, 28, e26, 10.1097/00006676-200401000-00023
Bernstorff von, 2001, Systemic and local immunosuppression in pancreatic cancer patients, Clin Can Res, 7, 925s
Zhang, 2014, CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice, Cancer Immunol Res, 2, 423, 10.1158/2326-6066.CIR-14-0016-T
Feig, 2013, Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer, Proc Natl Acad Sci U S A, 110, 20212, 10.1073/pnas.1320318110
Zhu, 2014, CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models, Cancer Res, 74, 5057, 10.1158/0008-5472.CAN-13-3723
Sherman, 2014, Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy, Cell, 159, 80, 10.1016/j.cell.2014.08.007
Olive, 2009, Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer, Science, 324, 1457, 10.1126/science.1171362
Pylayeva-Gupta, 2012, Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia, Cancer Cell, 21, 836, 10.1016/j.ccr.2012.04.024
Curran, 2010, 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 U S A, 107, 4275, 10.1073/pnas.0915174107
Leach, 1996, Enhancement of antitumor immunity by CTLA-4 blockade, Science, 271, 1734, 10.1126/science.271.5256.1734
Mangsbo, 2010, Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy, J Immunother, 33, 225, 10.1097/CJI.0b013e3181c01fcb
Williams, 2013, Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model, Clin Can Res, 19, 3545, 10.1158/1078-0432.CCR-12-3226
Sandin, 2014, Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo, Oncoimmunology, 3, e27614, 10.4161/onci.27614
Nomi, 2007, Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer, Clin Can Res, 13, 2151, 10.1158/1078-0432.CCR-06-2746
Jones, 2008, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science, 321, 1801, 10.1126/science.1164368
Soares, 2015, PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors, J Immunother, 38, 1, 10.1097/CJI.0000000000000062
Lutz, 2014, Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation, Can Immunol Res, 2, 616, 10.1158/2326-6066.CIR-14-0027
Ho, 2014, Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ, Cancer Res, 74, 3205, 10.1158/0008-5472.CAN-13-3461
Richman, 2014, Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer, Cancer Immunol Res, 2, 19, 10.1158/2326-6066.CIR-13-0152
Velcheti, 2013, Programmed death ligand-1 expression in non–small cell lung cancer, Lab Invest, 94, 107, 10.1038/labinvest.2013.130