Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options

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

Siegel, 2018, Cancer statistics, 2018, CA Cancer J Clin, 68, 7, 10.3322/caac.21442

Siegel, 2017, Cancer statistics, 2017, CA Cancer J Clin, 67, 7, 10.3322/caac.21387

Kleeff, 2016, Pancreatic cancer, Nat Rev Dis Prim, 2, 1, 10.1038/nrdp.2016.22

Neesse, 2015, Stromal biology and therapy in pancreatic cancer: a changing paradigm, Gut, 64, 1476, 10.1136/gutjnl-2015-309304

Hidalgo, 2010, Pancreatic cancer, N Engl J Med, 362, 1605, 10.1056/NEJMra0901557

Ko, 2016, A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma, Clin Cancer Res, 22, 61, 10.1158/1078-0432.CCR-15-0979

Bedard, 2015, A Phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors, Clin Cancer Res, 21, 730, 10.1158/1078-0432.CCR-14-1814

Tolcher, 2015, A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors, Ann Oncol, 26, 58, 10.1093/annonc/mdu482

Wolpin, 2009, Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer, J Clin Oncol, 27, 193, 10.1200/JCO.2008.18.9514

Infante, 2014, A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas, Eur J Cancer, 50, 2072, 10.1016/j.ejca.2014.04.024

Bodoky, 2012, A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy, Invest New Drugs, 30, 1216, 10.1007/s10637-011-9687-4

Conroy, 2011, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N Engl J Med, 364, 1817, 10.1056/NEJMoa1011923

Von Hoff, 2013, Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N Engl J Med, 369, 1691, 10.1056/NEJMoa1304369

Goldstein, 2015, Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial, J Natl Cancer Inst, 107, 10.1093/jnci/dju413

Ferlay, 2015, Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012, Int J Cancer, 136, E359, 10.1002/ijc.29210

Housman, 2014, Drug resistance in cancer: an overview, Cancers, 6, 1769, 10.3390/cancers6031769

Groenendijk, 2014, Drug resistance to targeted therapies: Déjà vu all over again, Mol Oncol, 8, 1067, 10.1016/j.molonc.2014.05.004

Hodi, 2010, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, 363, 711, 10.1056/NEJMoa1003466

Ribas, 2015, Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial, Lancet Oncol, 16, 908, 10.1016/S1470-2045(15)00083-2

Robert, 2015, Pembrolizumab versus ipilimumab in advanced melanoma, N Engl J Med, 372, 2521, 10.1056/NEJMoa1503093

Weber, 2015, 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, 16, 375, 10.1016/S1470-2045(15)70076-8

Rizvi, 2015, Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial, Lancet Oncol, 16, 257, 10.1016/S1470-2045(15)70054-9

Garon, 2015, Pembrolizumab for the treatment of non-small-cell lung cancer, N Engl J Med, 372, 2018, 10.1056/NEJMoa1501824

Reck, 2016, Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer, N Engl J Med, 375, 1823, 10.1056/NEJMoa1606774

Borghaei, 2015, Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer, N Engl J Med, 373, 1627, 10.1056/NEJMoa1507643

Taylor, 2015, Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032, J Immunother Cancer, 3, P376, 10.1186/2051-1426-3-S2-P376

Motzer, 2015, Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial, J Clin Oncol, 33, 1430, 10.1200/JCO.2014.59.0703

Weinstock, 2015, Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma, Ther Adv Urol, 7, 365, 10.1177/1756287215597647

Powles, 2014, MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer, Nature, 515, 558, 10.1038/nature13904

Powles, 2017, Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma, JAMA Oncol, 3, e172411, 10.1001/jamaoncol.2017.2411

Massard, 2016, Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer, J Clin Oncol, 34, 3119, 10.1200/JCO.2016.67.9761

Seiwert, 2015, Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): preliminary results from KEYNOTE-012 expansion cohort, J Clin Oncol, 33, LBA6008, 10.1200/jco.2015.33.18_suppl.lba6008

Seiwert, 2016, Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial, Lancet Oncol, 17, 956, 10.1016/S1470-2045(16)30066-3

Ansell, 2015, PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma, N Engl J Med, 372, 311, 10.1056/NEJMoa1411087

Armand, 2016, Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure, J Clin Oncol, 34, 3733, 10.1200/JCO.2016.67.3467

Lesokhin, 2016, Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study, J Clin Oncol, 34, 2698, 10.1200/JCO.2015.65.9789

Brahmer, 2012, Safety and activity of anti-PD-L1 antibody in patients with advanced cancer, N Engl J Med, 366, 2455, 10.1056/NEJMoa1200694

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

Pardoll, 2012, The blockade of immune checkpoints in cancer immunotherapy, Nat Rev Cancer, 12, 252, 10.1038/nrc3239

Gao, 2002, Molecular coordination of αβ T-cell receptors and coreceptors CD8 and CD4 in their recognition of peptide-MHC ligands, Trends Immunol, 23, 408, 10.1016/S1471-4906(02)02282-2

Steimle, 1994, Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA, Science, 265, 106, 10.1126/science.8016643

Stout, 1989, Antigen-specific activation of effector macrophages by IFN-gamma producing (TH1) T cell clones. Failure of IL-4-producing (TH2) T cell clones to activate effector function in macrophages, J Immunol, 142, 760, 10.4049/jimmunol.142.3.760

Dobrzanski, 2013, Expanding roles for CD4 T cells and their subpopulations in tumor immunity and therapy, Front Oncol, 3, 63, 10.3389/fonc.2013.00063

DeNardo, 2009, CD4+T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages, Cancer Cell, 16, 91, 10.1016/j.ccr.2009.06.018

Tanaka, 2017, Regulatory T cells in cancer immunotherapy, Cell Res, 27, 109, 10.1038/cr.2016.151

Crespo, 2013, T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment, Curr Opin Immunol, 25, 214, 10.1016/j.coi.2012.12.003

Topalian, 2015, Immune checkpoint blockade: a common denominator approach to cancer therapy, Cancer Cell, 27, 451, 10.1016/j.ccell.2015.03.001

Iwai, 2017, Cancer immunotherapies targeting the PD-1 signaling pathway, J Biomed Sci, 24, 26, 10.1186/s12929-017-0329-9

Schwartz, 1992, Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy, Cell, 71, 1065, 10.1016/S0092-8674(05)80055-8

Linsley, 1994, Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors, Immunity, 1, 793, 10.1016/S1074-7613(94)80021-9

Qureshi, 2011, Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4, Science, 332, 600, 10.1126/science.1202947

Krummel, 1996, CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells, J Exp Med, 183, 2533, 10.1084/jem.183.6.2533

Fallarino, 1998, B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28, J Exp Med, 188, 205, 10.1084/jem.188.1.205

Chambers, 1998, Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells, Eur J Immunol, 28, 3137, 10.1002/(SICI)1521-4141(199810)28:10<3137::AID-IMMU3137>3.0.CO;2-X

Takahashi, 2000, Immunologic self-tolerance maintained by Cd25+ Cd4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4, J Exp Med, 192, 303, 10.1084/jem.192.2.303

Hori, 2003, Control of regulatory T cell development by the transcription factor Foxp3, Science, 299, 1057, 10.1126/science.1079490

Fontenot, 2003, Foxp3 programs the development and function of CD4+CD25+ regulatory T cells, Nat Immunol, 4, 330, 10.1038/ni904

Wing, 2008, CTLA-4 control over Foxp3+ regulatory T cell function, Science, 322, 271, 10.1126/science.1160062

Klocke, 2017, CTLA-4 expressed by FOXP3+ regulatory T cells prevents inflammatory tissue attack and not T-cell priming in arthritis, Immunology, 152, 125, 10.1111/imm.12754

Bengsch, 2017, CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer, Cancer Immunol Immunother, 66, 1609, 10.1007/s00262-017-2053-4

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

Ishida, 1992, Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death, EMBO J, 11, 3887, 10.1002/j.1460-2075.1992.tb05481.x

Freeman, 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, 1027, 10.1084/jem.192.7.1027

Dong, 1999, B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion, Nat Med, 5, 1365, 10.1038/70932

Latchman, 2001, PD-L2 is a second ligand for PD-1 and inhibits T cell activation, Nat Immunol, 2, 261, 10.1038/85330

Tseng, 2001, B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells, J Exp Med, 193, 839, 10.1084/jem.193.7.839

Agata, 1996, Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes, Int Immunol, 8, 765, 10.1093/intimm/8.5.765

Youngblood, 2011, Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells, Immunity, 35, 400, 10.1016/j.immuni.2011.06.015

Iwai, 2003, PD-1 inhibits antiviral immunity at the effector phase in the liver, J Exp Med, 198, 39, 10.1084/jem.20022235

Barber, 2006, Restoring function in exhausted CD8 T cells during chronic viral infection, Nature, 439, 682, 10.1038/nature04444

Staron, 2014, The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection, Immunity, 41, 802, 10.1016/j.immuni.2014.10.013

Asano, 2017, PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy, Blood, 129, 2186, 10.1182/blood-2016-09-741629

Wang, 2008, Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+ CD4+ regulatory T cells, Proc Natl Acad Sci U S A, 105, 9331, 10.1073/pnas.0710441105

Wang, 2014, In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates, Cancer Immunol Res, 2, 846, 10.1158/2326-6066.CIR-14-0040

Nishimura, 1999, Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor, Immunity, 11, 141, 10.1016/S1074-7613(00)80089-8

Nishimura, 2001, Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice, Science, 291, 319, 10.1126/science.291.5502.319

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

Waterhouse, 1995, Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4, Science, 270, 985, 10.1126/science.270.5238.985

Keir, 2008, PD-1 and its ligands in tolerance and immunity, Annu Rev Immunol, 26, 677, 10.1146/annurev.immunol.26.021607.090331

Linsley, 1996, Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement, Immunity, 4, 535, 10.1016/S1074-7613(00)80480-X

Davoodzadeh Gholami, 2017, Exhaustion of T lymphocytes in the tumor microenvironment: significance and effective mechanisms, Cell Immunol, 322, 1, 10.1016/j.cellimm.2017.10.002

Topalian, 2012, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer, N Engl J Med, 366, 2443, 10.1056/NEJMoa1200690

Larkin, 2015, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, N Engl J Med, 373, 23, 10.1056/NEJMoa1504030

Ehrlich, 1960, Vol. II. Immunology and cancer research, Collected Papers of Paul Ehrlich: In Four Volumes Including a Complete Bibliography

Burnet, 1971, Immunological surveillance in neoplasia, Immunol Rev, 7, 3, 10.1111/j.1600-065X.1971.tb00461.x

Thomas, 1982, On immunosurveillance in human cancer, Yale J Biol Med, 55, 329

Dunn, 2002, Cancer immunoediting: from immunosurveillance to tumor escape, Nat Immunol, 3, 991, 10.1038/ni1102-991

Dunn, 2004, The three Es of cancer immunoediting, Annu Rev Immunol, 22, 329, 10.1146/annurev.immunol.22.012703.104803

Gopinathan, 2015, GEMMs as preclinical models for testing pancreatic cancer therapies, Dis Model Mech, 8, 1185, 10.1242/dmm.021055

Hingorani, 2003, Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse, Cancer Cell, 4, 437, 10.1016/S1535-6108(03)00309-X

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

Evans, 2016, Lack of immunoediting in murine pancreatic cancer reversed with neoantigen, JCI Insight, 1, 10.1172/jci.insight.88328

Foley, 2016, Current progress in immunotherapy for pancreatic cancer, Cancer Lett, 381, 244, 10.1016/j.canlet.2015.12.020

Hiraoka, 2006, Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions, Clin Cancer Res, 12, 5423, 10.1158/1078-0432.CCR-06-0369

Vonderheide, 2018, The immune revolution: a case for priming, not checkpoint, Cancer Cell, 33, 563, 10.1016/j.ccell.2018.03.008

Beatty, 2015, Immune escape mechanisms as a guide for cancer immunotherapy, Clin Cancer Res, 21, 687, 10.1158/1078-0432.CCR-14-1860

Yarchoan, 2017, Targeting neoantigens to augment antitumour immunity, Nat Rev Cancer, 17, 209, 10.1038/nrc.2016.154

Topalian, 2016, Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy, Nat Rev Cancer, 16, 275, 10.1038/nrc.2016.36

Coulie, 2014, Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy, Nat Rev Cancer, 14, 135, 10.1038/nrc3670

Campbell, 2017, Comprehensive analysis of hypermutation in human cancer, Cell, 171, 1042.e, 10.1016/j.cell.2017.09.048

Vogelstein, 2013, Cancer genome landscapes, Science, 339, 1546, 10.1126/science.1235122

Goodman, 2017, Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers, Mol Cancer Ther, 16, 2598, 10.1158/1535-7163.MCT-17-0386

Rizvi, 2015, Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Science, 348, 124, 10.1126/science.aaa1348

Yarchoan, 2017, Tumor mutational burden and response rate to PD-1 inhibition, N Engl J Med, 377, 2500, 10.1056/NEJMc1713444

Le, 2017, Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Science, 357, 409, 10.1126/science.aan6733

Germano, 2017, Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth, Nature, 552, 1, 10.1038/nature24673

Humphris, 2017, Hypermutation in pancreatic cancer, Gastroenterology, 152, 68.e, 10.1053/j.gastro.2016.09.060

Brown, 2018, Combining DNA damaging therapeutics with immunotherapy: more haste, less speed, Br J Cancer, 118, 312, 10.1038/bjc.2017.376

Lawrence, 2013, Mutational heterogeneity in cancer and the search for new cancer-associated genes, Nature, 499, 214, 10.1038/nature12213

Balachandran, 2017, Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer, Nature, 551, S12, 10.1038/nature24462

de Charette, 2016, Turning tumour cells into antigen presenting cells: the next step to improve cancer immunotherapy?, Eur J Cancer, 68, 134, 10.1016/j.ejca.2016.09.010

Delp, 2000, Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin, Bone Marrow Transplant, 25, S88, 10.1038/sj.bmt.1702363

Herrmann, 2004, HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway, Cancer Res, 64, 215, 10.1158/0008-5472.CAN-2522-2

Paulson, 2014, Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma, Cancer Immunol Res, 2, 1071, 10.1158/2326-6066.CIR-14-0005

Leone, 2013, MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells, J Natl Cancer Inst, 105, 1172, 10.1093/jnci/djt184

Lohmann, 1996, Multiple levels of MHC class I down-regulation by ras oncogenes, Scand J Immunol, 43, 537, 10.1046/j.1365-3083.1996.d01-73.x

Seliger, 1996, Suppression of MHC class I antigens in oncogenic transformants: association with decreased recognition by cytotoxic T lymphocytes, Exp Hematol, 24, 1275

Mimura, 2013, The MAPK pathway is a predominant regulator of HLA-A expression in esophageal and gastric cancer, J Immunol, 191, 6261, 10.4049/jimmunol.1301597

Pommier, 2018, Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases, Science, 360, eaao4908, 10.1126/science.aao4908

Snyder, 2014, Genetic basis for clinical response to CTLA-4 blockade in melanoma, N Engl J Med, 371, 2189, 10.1056/NEJMoa1406498

Van Allen, 2015, Genomic correlates of response to CTLA-4 blockade in metastatic melanoma, Science, 350, 207, 10.1126/science.aad0095

Hugo, 2016, Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma, Cell, 165, 35, 10.1016/j.cell.2016.02.065

Bailey, 2016, Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma, Sci Rep, 6, 1, 10.1038/srep35848

Balli, 2017, Immune cytolytic activity stratifies molecular subsets of human pancreatic cancer, Clin Cancer Res, 23, 3129, 10.1158/1078-0432.CCR-16-2128

Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat Med, 17, 500, 10.1038/nm.2344

Moffitt, 2015, Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma, Nat Genet, 47, 1168, 10.1038/ng.3398

Biankin, 2012, Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes, Nature, 491, 399, 10.1038/nature11547

Waddell, 2015, Whole genomes redefine the mutational landscape of pancreatic cancer, Nature, 518, 495, 10.1038/nature14169

Bailey, 2016, Genomic analyses identify molecular subtypes of pancreatic cancer, Nature, 531, 47, 10.1038/nature16965

Rooney, 2015, Molecular and genetic properties of tumors associated with local immune cytolytic activity, Cell, 160, 48, 10.1016/j.cell.2014.12.033

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

McAllister, 2014, Oncogenic kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia, Cancer Cell, 25, 621, 10.1016/j.ccr.2014.03.014

Vonderheide, 2014, Tumor-promoting inflammatory networks in pancreatic neoplasia: another reason to loathe kras, Cancer Cell, 25, 553, 10.1016/j.ccr.2014.04.020

Zhang, 2018, Precision immuno-oncology: prospects of individualized immunotherapy for pancreatic cancer, Cancers (Basel), 10, 39, 10.3390/cancers10020039

Lastwika, 2016, Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer, Cancer Res, 76, 227, 10.1158/0008-5472.CAN-14-3362

Parsa, 2007, Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma, Nat Med, 13, 84, 10.1038/nm1517

Casey, 2016, MYC regulates the antitumor immune response through CD47 and PD-L1, Science, 352, 227, 10.1126/science.aac9935

Feng, 2017, Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells, Oncogene, 36, 5829, 10.1038/onc.2017.188

Zhang, 2017, Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer, Gut, 66, 124, 10.1136/gutjnl-2016-312078

Hamid, 2013, Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma, N Engl J Med, 369, 134, 10.1056/NEJMoa1305133

Khandelwal, 2015, A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes, EMBO Mol Med, 7, 450, 10.15252/emmm.201404414

Lim, 2016, Deubiquitination and stabilization of PD-L1 by CSN5, Cancer Cell, 30, 925, 10.1016/j.ccell.2016.10.010

Lu, 2017, The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion, J Natl Cancer Inst, 109, 10.1093/jnci/djw283

Dunn, 2005, A critical function for type I interferons in cancer immunoediting, Nat Immunol, 6, 722, 10.1038/ni1213

Gao, 2016, Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy, Cell, 167, 397.e, 10.1016/j.cell.2016.08.069

Patel, 2017, Identification of essential genes for cancer immunotherapy, Nature, 548, 537, 10.1038/nature23477

Mandai, 2016, Dual faces of ifnγ in cancer progression: a role of pd-l1 induction in the determination of pro and antitumor immunity, Clin Cancer Res, 22, 2329, 10.1158/1078-0432.CCR-16-0224

Shin, 2017, Primary resistance to PD-1 blockade mediated by JAK1/2 mutations, Cancer Discov, 7, 188, 10.1158/2159-8290.CD-16-1223

Cogdill, 2017, Hallmarks of response to immune checkpoint blockade, Br J Cancer, 117, 1, 10.1038/bjc.2017.136

Mellor, 2008, Creating immune privilege: active local suppression that benefits friends, but protects foes, Nat Rev Immunol, 8, 74, 10.1038/nri2264

Highfill, 2014, Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy, Sci Transl Med, 6, 237ra67, 10.1126/scitranslmed.3007974

Lesokhin, 2012, Monocytic CCR2+ myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment, Cancer Res, 72, 876, 10.1158/0008-5472.CAN-11-1792

Hwang, 2008, Cancer-associated stromal fibroblasts promote pancreatic tumor progression, Cancer Res, 68, 918, 10.1158/0008-5472.CAN-07-5714

Özdemir, 2014, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell, 25, 719, 10.1016/j.ccr.2014.04.005

Carstens, 2017, Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer, Nat Commun, 8, 15095, 10.1038/ncomms15095

Ene-Obong, 2013, Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma, Gastroenterology, 145, 1121, 10.1053/j.gastro.2013.07.025

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

Johnson, 2017, Strategies for increasing pancreatic tumor immunogenicity, Clin Cancer Res, 23, 1656, 10.1158/1078-0432.CCR-16-2318

Jiang, 2016, Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy, Nat Med, 22, 851, 10.1038/nm.4123

Infante, 2012, Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors, J Clin Oncol, 30, 1527, 10.1200/JCO.2011.38.9346

Jones, 2015, A phase i study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors, Invest New Drugs, 33, 1100, 10.1007/s10637-015-0282-y

Soria, 2016, A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors, Ann Oncol, 27, 2268, 10.1093/annonc/mdw427

Lesina, 2011, Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer, Cancer Cell, 19, 456, 10.1016/j.ccr.2011.03.009

Fukuda, 2011, Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression, Cancer Cell, 19, 441, 10.1016/j.ccr.2011.03.002

Kang, 2012, The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia, Proc Natl Acad Sci U S A, 109, 7031, 10.1073/pnas.1113865109

Zhang, 2013, Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance, Cancer Res, 73, 6359, 10.1158/0008-5472.CAN-13-1558-T

Angevin, 2014, A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors, Clin Cancer Res, 20, 2192, 10.1158/1078-0432.CCR-13-2200

Mace, 2018, IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer, Gut, 67, 320, 10.1136/gutjnl-2016-311585

Sato, 2016, Role of hyaluronan in pancreatic cancer biology and therapy: once again in the spotlight, Cancer Sci, 107, 569, 10.1111/cas.12913

Cheng, 2013, Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma, PLoS One, 8, e80765, 10.1371/journal.pone.0080765

Jacobetz, 2013, Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer, Gut, 62, 112, 10.1136/gutjnl-2012-302529

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

Thompson, 2010, Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models, Mol Cancer Ther, 9, 3052, 10.1158/1535-7163.MCT-10-0470

Singha, 2015, Tumor-associated hyaluronan limits efficacy of monoclonal antibody therapy, Mol Cancer Ther, 14, 523, 10.1158/1535-7163.MCT-14-0580

Blache, 2012, Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth, Cancer Res, 72, 6447, 10.1158/0008-5472.CAN-12-0193

Manuel, 2015, Salmonella-based therapy targeting indoleamine 2,3-dioxygenase coupled with enzymatic depletion of tumor hyaluronan induces complete regression of aggressive pancreatic tumors, Cancer Immunol Res, 3, 1096, 10.1158/2326-6066.CIR-14-0214

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

Kumar, 2016, The nature of myeloid-derived suppressor cells in the tumor microenvironment, Trends Immunol, 37, 208, 10.1016/j.it.2016.01.004

Sica, 2008, Macrophage polarization in tumour progression, Semin Cancer Biol, 18, 349, 10.1016/j.semcancer.2008.03.004

Ino, 2013, Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer, Br J Cancer, 108, 914, 10.1038/bjc.2013.32

Protti, 2013, Immune infiltrates as predictive markers of survival in pancreatic cancer patients, Front Physiol, 4, 210, 10.3389/fphys.2013.00210

Monu, 2012, Myeloid-derived suppressor cells and anti-tumor T cells: a complex relationship, Immunol Invest, 41, 595, 10.3109/08820139.2012.673191

Shibuya, 2014, Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment, PLoS One, 9, e96565, 10.1371/journal.pone.0096565

Tassi, 2008, Carcinoembryonic antigen-specific but not antiviral CD4+ T cell immunity is impaired in pancreatic carcinoma patients, J Immunol, 181, 6595, 10.4049/jimmunol.181.9.6595

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

Soares, 2015, TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner, Oncotarget, 6, 43005, 10.18632/oncotarget.5656

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

Leliefeld, 2015, How neutrophils shape adaptive immune responses, Front Immunol, 6, 471, 10.3389/fimmu.2015.00471

Quezada, 2004, CD40/CD154 interactions at the interface of tolerance and immunity, Annu Rev Immunol, 22, 307, 10.1146/annurev.immunol.22.012703.104533

Schoenberger, 1998, T-cell help for cytotoxic T-lymphocytes is mediated by CD40-CD40L interactions, Nature, 393, 480, 10.1038/31002

Bennett, 1998, Help for cytotoxic-T-cell responses is mediated by CD40 signalling, Nature, 393, 478, 10.1038/30996

Ridge, 1998, A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell, Nature, 393, 474, 10.1038/30989

French, 1999, CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help, Nat Med, 5, 548, 10.1038/8426

Diehl, 1999, CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy, Nat Med, 5, 774, 10.1038/10495

Sotomayor, 1999, Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of cd40, Nat Med, 5, 780, 10.1038/10503

Beatty, 2011, CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans, Science, 331, 1612, 10.1126/science.1198443

Beatty, 2015, Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages, Gastroenterology, 149, 201, 10.1053/j.gastro.2015.04.010

Vonderheide, 2013, Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors, Oncoimmunology, 2, e23033, 10.4161/onci.23033

Vonderheide, 2007, Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody, J Clin Oncol, 25, 876, 10.1200/JCO.2006.08.3311

Nowak, 2015, A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma, Ann Oncol, 26, 2483, 10.1093/annonc/mdv387

Beatty, 2013, A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma, Clin Cancer Res, 19, 6286, 10.1158/1078-0432.CCR-13-1320

Byrne, 2016, CD40 stimulation obviates innate sensors and drives T cell immunity in cancer, Cell Rep, 15, 2719, 10.1016/j.celrep.2016.05.058

Acosta, 2008, Chemokine signaling via the CXCR2 receptor reinforces senescence, Cell, 133, 1006, 10.1016/j.cell.2008.03.038

Lesina, 2016, RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis, J Clin Invest, 126, 2919, 10.1172/JCI86477

Cacalano, 1994, Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog, Science, 265, 682, 10.1126/science.8036519

Eash, 2010, CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow, J Clin Invest, 120, 2423, 10.1172/JCI41649

Chao, 2016, CXCR2-dependent accumulation of tumor-associated neutrophils regulates T-cell immunity in pancreatic ductal adenocarcinoma, Cancer Immunol Res, 4, 968, 10.1158/2326-6066.CIR-16-0188

Kaneider, 2005, Reversing systemic inflammatory response syndrome with chemokine receptor pepducins, Nat Med, 11, 661, 10.1038/nm1245

Jamieson, 2012, Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis, J Clin Invest, 122, 3127, 10.1172/JCI61067

Nicholls, 2015, Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist, J Pharmacol Exp Ther, 353, 340, 10.1124/jpet.114.221358

Steele, 2016, CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma, Cancer Cell, 29, 832, 10.1016/j.ccell.2016.04.014

Stromnes, 2015, T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma, Cancer Cell, 28, 638, 10.1016/j.ccell.2015.09.022

Lin, 2001, Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy, J Exp Med, 193, 727, 10.1084/jem.193.6.727

Cannarile, 2017, Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy, J Immunother Cancer, 5, 53, 10.1186/s40425-017-0257-y

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

Kumar, 2017, Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors, Cancer Cell, 32, 654, 10.1016/j.ccell.2017.10.005

Zhou, 2018, Neutrophils and PMN-MDSC: their biological role and interaction with stromal cells, Semin Immunol, 35, 19, 10.1016/j.smim.2017.12.004

Sagiv-Barfi, 2015, Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK, Proc Natl Acad Sci U S A, 112, E966, 10.1073/pnas.1500712112

Masso-Valles, 2015, Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma, Cancer Res, 75, 1675, 10.1158/0008-5472.CAN-14-2852

Gunderson, 2016, Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer, Cancer Discov, 6, 270, 10.1158/2159-8290.CD-15-0827

Dubovsky, 2013, Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes, Blood, 122, 2539, 10.1182/blood-2013-06-507947

Zou, 2017, γδ T cells in cancer immunotherapy, Oncotarget, 8, 8900, 10.18632/oncotarget.13051

Tanaka, 1995, Natural and synthetic non-peptide antigens recognized by human γδ T cells, Nature, 375, 155, 10.1038/375155a0

Lawand, 2017, Key features of gamma-delta T-cell subsets in human diseases and their immunotherapeutic implications, Front Immunol, 8, 761, 10.3389/fimmu.2017.00761

Oberg, 2014, Novel bispecific antibodies increase GD T-cell cytotoxicity against pancreatic cancer cells, Cancer Res, 74, 1349, 10.1158/0008-5472.CAN-13-0675

Daley, 2016, γδ T cells support pancreatic oncogenesis by restraining αβ T cell activation, Cell, 166, 1485.e, 10.1016/j.cell.2016.07.046

Michalek, 2011, Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets, J Immunol, 186, 3299, 10.4049/jimmunol.1003613

van der Windt, 2012, Metabolic switching and fuel choice during T-cell differentiation and memory development, Immunol Rev, 249, 27, 10.1111/j.1600-065X.2012.01150.x

Wang, 2011, The transcription factor myc controls metabolic reprogramming upon T lymphocyte activation, Immunity, 35, 871, 10.1016/j.immuni.2011.09.021

Chang, 2013, Posttranscriptional control of T cell effector function by aerobic glycolysis, Cell, 153, 1239, 10.1016/j.cell.2013.05.016

Zheng, 2009, Anergic T cells are metabolically anergic, J Immunol, 183, 6095, 10.4049/jimmunol.0803510

Renner, 2017, Metabolic hallmarks of tumor and immune cells in the tumor microenvironment, Front Immunol, 8, 248, 10.3389/fimmu.2017.00248

Chang, 2015, Metabolic competition in the tumor microenvironment is a driver of cancer progression, Cell, 162, 1229, 10.1016/j.cell.2015.08.016

Carr, 2010, Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation, J Immunol, 185, 1037, 10.4049/jimmunol.0903586

Speiser, 2016, Regulatory circuits of T cell function in cancer, Nat Rev Immunol, 16, 599, 10.1038/nri.2016.80

Rodriguez, 2005, Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma, J Exp Med, 202, 931, 10.1084/jem.20050715

Rodriguez, 2009, Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes, Cancer Res, 69, 1553, 10.1158/0008-5472.CAN-08-1921

Löb, 2009, IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism, Cancer Immunol Immunother, 58, 153, 10.1007/s00262-008-0513-6

Braun, 2005, A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation, Blood, 106, 2375, 10.1182/blood-2005-03-0979

Uyttenhove, 2003, Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase, Nat Med, 9, 1269, 10.1038/nm934

Munn, 1999, Inhibition of t cell proliferation by macrophage tryptophan catabolism, J Exp Med, 189, 1363, 10.1084/jem.189.9.1363

Fallarino, 2002, T cell apoptosis by tryptophan catabolism, Cell Death Differ, 9, 1069, 10.1038/sj.cdd.4401073

Platten, 2012, Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion, Cancer Res, 72, 5435, 10.1158/0008-5472.CAN-12-0569

Fischer, 2007, Inhibitory effect of tumor cell-derived lactic acid on human T cells, Blood, 109, 3812, 10.1182/blood-2006-07-035972

Mendler, 2012, Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation, Int J Cancer, 131, 633, 10.1002/ijc.26410

Calcinotto, 2012, Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes, Cancer Res, 72, 2746, 10.1158/0008-5472.CAN-11-1272

Huang, 1997, Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion, Blood, 90, 1600, 10.1182/blood.V90.4.1600

Ohta, 2014, Extracellular adenosine-mediated modulation of regulatory T cells, Front Immunol, 5, 10.3389/fimmu.2014.00304

Ohta, 2016, A metabolic immune checkpoint: adenosine in tumor microenvironment, Front Immunol, 7, 1, 10.3389/fimmu.2016.00109

Sreeramkumar, 2012, Prostaglandin E2 and T cells: friends or foes?, Immunol Cell Biol, 90, 579, 10.1038/icb.2011.75

Halbrook, 2017, Employing metabolism to improve the diagnosis and treatment of pancreatic cancer, Cancer Cell, 31, 5, 10.1016/j.ccell.2016.12.006

Mueller, 2014, Cachexia and pancreatic cancer: are there treatment options?, World J Gastroenterol, 20, 9361, 10.3748/wjg.v20.i28.9361

Flint, 2016, Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity, Cell Metab, 24, 672, 10.1016/j.cmet.2016.10.010

Bonetto, 2011, STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia, PLoS One, 6, e22538, 10.1371/journal.pone.0022538

Bonetto, 2012, JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia, Am J Physiol Endocrinol Metab, 303, E410, 10.1152/ajpendo.00039.2012

Gotwals, 2017, Prospects for combining targeted and conventional cancer therapy with immunotherapy, Nat Rev Cancer, 17, 286, 10.1038/nrc.2017.17

Ruess, 2017, Pharmacotherapeutic management of pancreatic ductal adenocarcinoma: current and emerging concepts, Drugs Aging, 34, 331, 10.1007/s40266-017-0453-y

Zheng, 2015, Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer, Cell Immunol, 294, 54, 10.1016/j.cellimm.2015.02.003

Kim, 2016, Stereotactic body radiotherapy for the pancreas: a critical review for the medical oncologist, J Gastrointest Oncol, 7, 479, 10.21037/jgo.2015.10.01

Kalina, 2017, Immune modulation by androgen deprivation and radiation therapy: implications for prostate cancer immunotherapy, Cancers, 9, 13, 10.3390/cancers9020013

Burnette, 2013, Radiation as an immune modulator, Semin Radiat Oncol, 23, 273, 10.1016/j.semradonc.2013.05.009

Postow, 2012, Immunologic correlates of the abscopal effect in a patient with melanoma, N Engl J Med, 366, 925, 10.1056/NEJMoa1112824

Formenti, 2013, Combining radiotherapy and cancer immunotherapy: a paradigm shift, J Natl Cancer Inst, 105, 256, 10.1093/jnci/djs629

Golden, 2013, An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer, Cancer Immunol Res, 1, 365, 10.1158/2326-6066.CIR-13-0115

Deng, 2014, Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice, J Clin Invest, 124, 687, 10.1172/JCI67313

Lutz, 2014, Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation, Cancer Immunol Res, 2, 616, 10.1158/2326-6066.CIR-14-0027

Azad, 2017, PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy, EMBO Mol Med, 9, 167, 10.15252/emmm.201606674

Twyman-Saint Victor, 2015, Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer, Nature, 520, 373, 10.1038/nature14292

Rech, 2018, Radiotherapy and CD40 activation separately augment immunity to checkpoint blockade in cancer, Cancer Res, 78, 4282, 10.1158/0008-5472.CAN-17-3821

Wang, 2018, Combining immunotherapy and radiotherapy for cancer treatment: current challenges and future directions, Front Pharmacol, 9, 185, 10.3389/fphar.2018.00185

Naik, 2009, Engineering oncolytic viruses to exploit tumor specific defects in innate immune signaling pathways, Expert Opin Biol Ther, 9, 1163, 10.1517/14712590903170653

Chiocca, 2014, Oncolytic viruses and their application to cancer immunotherapy, Cancer Immunol Res, 2, 295, 10.1158/2326-6066.CIR-14-0015

Wong, 2010, Oncolytic viruses for cancer therapy: overcoming the obstacles, Viruses, 2, 78, 10.3390/v2010078

Pan, 2009, Utilizing Ras signaling pathway to direct selective replication of herpes simplex virus-1, PLoS One, 4, e6514, 10.1371/journal.pone.0006514

Doloff, 2008, Human telomerase reverse transcriptase promoter-driven oncolytic adenovirus with E1B-19 kDa and E1B-55 kDa gene deletions, Hum Gene Ther, 19, 1383, 10.1089/hum.2008.056

Nishimoto, 2009, Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob, Gene Ther, 16, 669, 10.1038/gt.2009.1

Conner, 2008, A strategy for systemic delivery of the oncolytic herpes virus HSV1716: redirected tropism by antibody-binding sites incorporated on the virion surface as a glycoprotein D fusion protein, Gene Ther, 15, 1579, 10.1038/gt.2008.121

Lichty, 2014, Going viral with cancer immunotherapy, Nat Rev Cancer, 14, 559, 10.1038/nrc3770

Sobol, 2011, Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy, Mol Ther, 19, 335, 10.1038/mt.2010.264

Janeway, 2002, Innate immune recognition, Annu Rev Immunol, 20, 197, 10.1146/annurev.immunol.20.083001.084359

Rahal, 2017, Oncolytic viral therapy for pancreatic cancer, J Surg Oncol, 116, 94, 10.1002/jso.24626

Mahalingam, 2018, A phase II study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma, Cancers, 10, 160, 10.3390/cancers10060160

Gujar, 2018, Antitumor benefits of antiviral immunity: an underappreciated aspect of oncolytic virotherapies, Trends Immunol, 39, 209, 10.1016/j.it.2017.11.006

Lutz, 2014, Priming the pancreatic cancer tumor microenvironment for checkpoint-inhibitor immunotherapy, Oncoimmunology, 3, e962401, 10.4161/21624011.2014.962401

Bourgeois-Daigneault, 2018, Neo-adjuvant oncolytic virotherapy prior to surgery sensitizes triple-negative breast cancer to immune checkpoint therapy, Sci Transl Med, 10, 1, 10.1126/scitranslmed.aao1641

Lee, 2018, Potentiating prostate cancer immunotherapy with oncolytic viruses, Nat Rev Urol, 15, 235, 10.1038/nrurol.2018.10

Samson, 2018, Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade, Sci Transl Med, 10, 10.1126/scitranslmed.aam7577

Blair, 2017, Rational combinations of immunotherapy for pancreatic ductal adenocarcinoma, Chin Clin Oncol, 6, 31, 10.21037/cco.2017.06.04

Skelton, 2017, Overcoming the resistance of pancreatic cancer to immune checkpoint inhibitors, J Surg Oncol, 116, 55, 10.1002/jso.24642

Jaffee, 2002, Focus on pancreas cancer, Cancer Cell, 2, 25, 10.1016/S1535-6108(02)00093-4

Melero, 2014, Therapeutic vaccines for cancer: an overview of clinical trials, Nat Rev Clin Oncol, 11, 509, 10.1038/nrclinonc.2014.111

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

Le, 2015, Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer, J Clin Oncol, 33, 1325, 10.1200/JCO.2014.57.4244

Abate-Daga, 2016, CAR models: next-generation CAR modifications for enhanced T-cell function, Mol Ther Oncolytics, 3, 16014, 10.1038/mto.2016.14

Marin-Acevedo, 2018, Cancer immunotherapy beyond immune checkpoint inhibitors, J Hematol Oncol, 11, 8, 10.1186/s13045-017-0552-6

Zhang, 2017, Engineering CAR-T cells, Biomark Res, 5, 22, 10.1186/s40364-017-0102-y

Dotti, 2014, Design and development of therapies using chimeric antigen receptor-expressing T cells, Immunol Rev, 257, 107, 10.1111/imr.12131

Kenderian, 2014, Chimeric antigen receptor T-cell therapy to target hematologic malignancies, Cancer Res, 74, 6383, 10.1158/0008-5472.CAN-14-1530

Brown, 2016, Next frontiers in CAR T-cell therapy, Mol Ther oncolytics, 3, 16028, 10.1038/mto.2016.28

Yu, 2017, Chimeric antigen receptor T cells: a novel therapy for solid tumors, J Hematol Oncol, 10, 78, 10.1186/s13045-017-0444-9

DeSelm, 2017, CAR T-cell therapy for pancreatic cancer, J Surg Oncol, 116, 63, 10.1002/jso.24627

Bauer, 2016, Prevailing over T cell exhaustion: new developments in the immunotherapy of pancreatic cancer, Cancer Lett, 381, 259, 10.1016/j.canlet.2016.02.057

Cherkassky, 2016, Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition, J Clin Invest, 126, 3130, 10.1172/JCI83092

Moon, 2014, Multifactorial T cell hypofunction that is reversible can limit the efficacy of chimeric antibody receptor-transduced human T cells in solid tumors, Clin Cancer Res, 20, 4262, 10.1158/1078-0432.CCR-13-2627

John, 2013, Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells, Clin Cancer Res, 19, 5636, 10.1158/1078-0432.CCR-13-0458

Suarez, 2016, Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model, Oncotarget, 7, 34341, 10.18632/oncotarget.9114

Li, 2017, Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors, Clin Cancer Res, 23, 6982, 10.1158/1078-0432.CCR-17-0867

Hall, 2016, Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors, J Immunother Cancer, 4, 61, 10.1186/s40425-016-0164-7

Rosenberg, 2011, Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy, Clin Cancer Res, 17, 4550, 10.1158/1078-0432.CCR-11-0116

Rusakiewicz, 2013, Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors, Cancer Res, 73, 3499, 10.1158/0008-5472.CAN-13-0371

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

Sideras, 2014, Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies, Cancer Treat Rev, 40, 513, 10.1016/j.ctrv.2013.11.005

Poschke, 2016, Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma, Oncoimmunology, 5, e1240859, 10.1080/2162402X.2016.1240859

Mullinax, 2018, Combination of ipilimumab and adoptive cell therapy with tumor-infiltrating lymphocytes for patients with metastatic melanoma, Front Oncol, 8, 44, 10.3389/fonc.2018.00044