Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Zappasodi, R., Merghoub, T. & Wolchok, J. D. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33, 581–598 (2018).
Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
Gettinger, S. et al. Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study. J. Clin. Oncol. 36, 1675–1684 (2018).
Fridman, W. H., Pages, F., Sautes-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).
Pages, F. et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J. Clin. Oncol. 27, 5944–5951 (2009).
Pages, F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).
Teng, M. W., Ngiow, S. F., Ribas, A. & Smyth, M. J. Classifying cancers based on T cell infiltration and PD-L1. Cancer Res. 75, 2139–2145 (2015).
Uno, T. et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat. Med. 12, 693–698 (2006).
Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol. 13, 143–158 (2016).
Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949 (2017).
Takeda, K. et al. IFN-gamma is required for cytotoxic T cell-dependent cancer genome immunoediting. Nat. Commun. 8, 14607 (2017).
Mandai, M. et al. Dual faces of IFNgamma in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity. Clin. Cancer Res. 22, 2329–2334 (2016).
Chang, C. C. et al. Multiple structural and epigenetic defects in the human leukocyte antigen class I antigen presentation pathway in a recurrent metastatic melanoma following immunotherapy. J. Biol. Chem. 290, 26562–26575 (2015).
Song, K. H. et al. HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells. Cancer Res. 77, 5039–5053 (2017).
Mittal, D., Gubin, M. M., Schreiber, R. D. & Smyth, M. J. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr. Opin. Immunol. 27, 16–25 (2014).
Teng, M. W., Galon, J., Fridman, W. H. & Smyth, M. J. From mice to humans: developments in cancer immunoediting. J. Clin. Invest. 125, 3338–3346 (2015).
O’Donnell, J. S., Long, G. V., Scolyer, R. A., Teng, M. W. & Smyth, M. J. Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat. Rev. 52, 71–81 (2017).
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).
Shin, D. S. et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017).
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Matsushita, H. et al. Cancer exome analysis reveals a T cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).
Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).
Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).
Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85 (2015).
Poschke, I. et al. Identification of a tumor-reactive T cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma. Oncoimmunology 5, e1240859 (2016).
Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).
Lee, C. H., Yelensky, R., Jooss, K. & Chan, T. A. Update on tumor neoantigens and their utility: why it is good to be different. Trends Immunol. 39, 536–548 (2018).
Montgomery, R. B., Makary, E., Schiffman, K., Goodell, V. & Disis, M. L. Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase. Cancer Res. 65, 650–656 (2005).
Goodell, V. et al. Level of HER-2/neu protein expression in breast cancer may affect the development of endogenous HER-2/neu-specific immunity. Mol. Cancer Ther. 7, 449–454 (2008).
Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Weinstein, J. N. et al. The Cancer Genome Atlas pan-cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).
Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 (2018).
Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).
Lauss, M. et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat. Commun. 8, 1738 (2017).
Smith, C. & Khanna, R. Adoptive cellular immunotherapy for virus-associated cancers: a new paradigm in personalized medicine. Immunol. Cell Biol. 95, 364–371 (2017).
Smith, C. et al. Effective treatment of metastatic forms of Epstein-Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer Res. 72, 1116–1125 (2012).
Duan, F. et al. Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. J. Exp. Med. 211, 2231–2248 (2014).
Luksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).
Kim, S. et al. Neopepsee: accurate genome-level prediction of neoantigens by harnessing sequence and amino acid immunogenicity information. Ann. Oncol. 29, 1030–1036 (2018).
Marty, R., Thompson, W. K., Salem, R. M., Zanetti, M. & Carter, H. Evolutionary pressure against MHC class II binding cancer mutations. Cell 175, 416–428 (2018).
Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, 439–442 (2013).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).
Carbone, D. P. et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017).
Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852 (2018).
Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
Davoli, T., Uno, H., Wooten, E. C. & Elledge, S. J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355, eaaf8399 (2017).
Angelova, M. et al. Evolution of metastases in space and time under immune selection. Cell 175, 751–765 (2018).
Jaffee, E. M. et al. Future cancer research priorities in the USA: a Lancet Oncology Commission. Lancet Oncol. 18, 653–706 (2017).
Spira, A. et al. Precancer atlas to drive precision prevention trials. Cancer Res. 77, 1510–1541 (2017).
Farrar, J. D. et al. Cancer dormancy. VII. A regulatory role for CD8+ T cells and IFN-gamma in establishing and maintaining the tumor-dormant state. J. Immunol. 162, 2842–2849 (1999).
Quesnel, B. Dormant tumor cells as a therapeutic target? Cancer Lett. 267, 10–17 (2008).
Manjili, M. H. The inherent premise of immunotherapy for cancer dormancy. Cancer Res. 74, 6745–6749 (2014).
Manjili, M. H. & Payne, K. K. Prospects in cancer immunotherapy: treating advanced stage disease or preventing tumor recurrence? Discov. Med. 19, 427–431 (2015).
McLaughlin-Drubin, M. E. & Munger, K. Viruses associated with human cancer. Biochim. Biophys. Acta 1782, 127–150 (2008).
Burd, E. M. Human papillomavirus and cervical cancer. Clin. Microbiol. Rev. 16, 1–17 (2003).
Neuveut, C., Wei, Y. & Buendia, M. A. Mechanisms of HBV-related hepatocarcinogenesis. J. Hepatol. 52, 594–604 (2010).
Sigl, V. et al. RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res. 26, 761–774 (2016).
Nolan, E. et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat. Med. 22, 933–939 (2016).
Patel, S. G. & Ahnen, D. J. Familial colon cancer syndromes: an update of a rapidly evolving field. Curr. Gastroenterol. Rep. 14, 428–438 (2012).
Chang, K. Lynch syndrome premalignancy upregulates immune checkpoints independently from neoantigen and mutational rates. Cancer Res. 78, 1256 (2018).
Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).
Gubin, M. M., Artyomov, M. N., Mardis, E. R. & Schreiber, R. D. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J. Clin. Invest. 125, 3413–3421 (2015).
Collins, J. M., Redman, J. M. & Gulley, J. L. Combining vaccines and immune checkpoint inhibitors to prime, expand, and facilitate effective tumor immunotherapy. Expert Rev. Vaccines 17, 697–705 (2018).
Huang, A. C. et al. T cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017).
Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).
Eggermont, A. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 16, 522–530 (2015).
Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018).
Sosa, M. S., Bragado, P. & Aguirre-Ghiso, J. A. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).
Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).
Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).
Forde, P. M. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378, 1976–1986 (2018).
Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).
Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).
Rozeman, E. A. et al. (Neo-)adjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage 3 melanoma — updated relapse free survival (RFS) data from the OpACIN trial and first biomarker analyses. Ann. Oncol. 28, mdx377.008 (2017).
Keung, E. Z., Ukponmwan, E. U., Cogdill, A. P. & Wargo, J. A. The rationale and emerging use of neoadjuvant immune checkpoint blockade for solid malignancies. Ann. Surg. Oncol. 25, 1814–1827 (2018).
Tetzlaff, M. T. et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann. Oncol. 29, 1861–1868 (2018).
Cortazar, P. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).
Petrelli, F. et al. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur. Urol. 65, 350–357 (2014).
Park, I. J. et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J. Clin. Oncol. 30, 1770–1776 (2012).
Lorenzen, S. et al. Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy. Ann. Oncol. 24, 2068–2073 (2013).
Ajani, J. A. et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J. Clin. Oncol. 23, 1237–1244 (2005).
Crowley, E., Di Nicolantonio, F., Loupakis, F. & Bardelli, A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10, 472–484 (2013).
Ayers, M. et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).
Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
Gajewski, T. F. et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr. Opin. Immunol. 25, 268–276 (2013).
Gajewski, T. F. The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).
Goodman, A. M. et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16, 2598–2608 (2017).
Ock, C. Y. et al. Pan-cancer immunogenomic perspective on the tumor microenvironment based on PD-L1 and CD8 T-cell infiltration. Clin. Cancer Res. 22, 2261–2270 (2016).
Taube, J. M. et al. 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 (2012).
Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).
Chen, Y. P. et al. Genomic analysis of tumor microenvironment immune types across 14 solid cancer types: immunotherapeutic implications. Theranostics 7, 3585–3594 (2017).
Prat, A. et al. Immune-related gene expression profiling after PD-1 blockade in non-small cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma. Cancer Res. 77, 3540–3550 (2017).
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Sun, C., Mezzadra, R. & Schumacher, T. N. Regulation and function of the PD-L1 checkpoint. Immunity 48, 434–452 (2018).
Payne, K. K. et al. Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells. J. Leukoc. Biol. 100, 625–635 (2016).
Chen, G. et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560, 382–386 (2018).
Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).
Kleffel, S. et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242–1256 (2015).
Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018).
Li, X. Y. et al. CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms. J. Clin. Invest. 128, 2613–2625 (2018).
Blake, S. J., Dougall, W. C., Miles, J. J., Teng, M. W. & Smyth, M. J. Molecular pathways: targeting CD96 and TIGIT for cancer immunotherapy. Clin. Cancer Res. 22, 5183–5188 (2016).
Blake, S. J. et al. Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discov. 6, 446–459 (2016).
Harjunpaa, H. et al. Deficiency of host CD96 and PD-1 or TIGIT enhances tumor immunity without significantly compromising immune homeostasis. Oncoimmunology 7, e1445949 (2018).
Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).
Neubert, N. J. et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci. Transl Med. 10, eaan3311 (2018).
Campoli, M. & Ferrone, S. HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene 27, 5869–5885 (2008).
Seliger, B. The link between MHC class I abnormalities of tumors, oncogenes, tumor suppressor genes, and transcription factors. J. Immunotoxicol. 11, 308–310 (2014).
Hicklin, D. J. et al. beta2-Microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma. J. Clin. Invest. 101, 2720–2729 (1998).
Restifo, N. P. et al. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J. Natl Cancer Inst. 88, 100–108 (1996).
Godfrey, D. I., Le Nours, J., Andrews, D. M., Uldrich, A. P. & Rossjohn, J. Unconventional T cell targets for cancer immunotherapy. Immunity 48, 453–473 (2018).
Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).
Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8, 1136 (2017).
Garrido, C. et al. Alterations of HLA class I expression in human melanoma xenografts in immunodeficient mice occur frequently and are associated with higher tumorigenicity. Cancer Immunol. Immunother. 59, 13–26 (2010).
Zeestraten, E. C. et al. Combined analysis of HLA class I, HLA-E and HLA-G predicts prognosis in colon cancer patients. Br. J. Cancer 110, 459–468 (2014).
Gooden, M. et al. HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8(+) T lymphocytes. Proc. Natl Acad. Sci. USA 108, 10656–10661 (2011).
Morandi, F. & Pistoia, V. Interactions between HLA-G and HLA-E in physiological and pathological conditions. Front. Immunol. 5, 394 (2014).
Dunn, G. P. et al. Interferon-gamma and cancer immunoediting. Immunol. Res. 32, 231–245 (2005).
Dighe, A. S., Richards, E., Old, L. J. & Schreiber, R. D. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1, 447–456 (1994).
Sharma, A. et al. HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ. Cancer 118, 4354–4362 (2012).
Kmieciak, M., Knutson, K. L., Dumur, C. I. & Manjili, M. H. HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses. Eur. J. Immunol. 37, 675–685 (2007).
Kaplan, M. H., Wurster, A. L. & Grusby, M. J. A signal transducer and activator of transcription (Stat)4-independent pathway for the development of T helper type 1 cells. J. Exp. Med. 188, 1191–1196 (1998).
Gao, J. et al. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397–404 (2016).
Rodig, S. J. et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl Med. 10, eaar3342 (2018).
Patel, S. J. et al. Identification of essential genes for cancer immunotherapy. Nature 548, 537–542 (2017).
Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418 (2017).
Kearney, C. J. et al. Tumor immune evasion arises through loss of TNF sensitivity. Sci. Immunol. 3, eaar3451 (2018).
Smyth, M. J., Kelly, J. M., Baxter, A. G., Korner, H. & Sedgwick, J. D. An essential role for tumor necrosis factor in natural killer cell-mediated tumor rejection in the peritoneum. J. Exp. Med. 188, 1611–1619 (1998).
Lickliter, J. D. et al. Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction. Br. J. Cancer 96, 600–608 (2007).
Vijayan, D., Young, A., Teng, M. W. L. & Smyth, M. J. Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer 17, 709–724 (2017).
Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103, 13132–13137 (2006).
Beavis, P. A. et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl Acad. Sci. USA 110, 14711–14716 (2013).
Young, A. et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 30, 391–403 (2016).
Chen, L. et al. CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov. 8, 1156–1175 (2018).
Triplett, T. A. et al. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat. Biotechnol. 36, 758–764 (2018).
Moon, Y. W., Hajjar, J., Hwu, P. & Naing, A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunother. Cancer 3, 51 (2015).
Cheong, J. E. & Sun, L. Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy — challenges and opportunities. Trends Pharmacol. Sci. 39, 307–325 (2018).
Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).
Johnston, C. J., Smyth, D. J., Dresser, D. W. & Maizels, R. M. TGF-beta in tolerance, development and regulation of immunity. Cell. Immunol. 299, 14–22 (2016).
David, J. M. et al. A novel bifunctional anti-PD-L1/TGF-beta Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology 6, e1349589 (2017).
Strauss, J. et al. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFbeta, in advanced solid tumors. Clin. Cancer Res. 24, 1287–1295 (2018).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Li, J. et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49, 178–193 (2018).
Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).
Sato, E. et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 18538–18543 (2005).
Naito, Y. et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 58, 3491–3494 (1998).
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).
Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).
Hu-Lieskovan, S., Homet Moreno, B. & Ribas, A. Excluding T cells: is beta-catenin the full story? Cancer Cell 27, 749–750 (2015).
Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).
Bald, T. et al. Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Discov. 4, 674–687 (2014).
Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015).
Adamus, T. & Kortylewski, M. The revival of CpG oligonucleotide-based cancer immunotherapies. Contemp. Oncol. 22, 56–60 (2018).
Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563 (2018).
Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).
Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013).
Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119 (2017).
Andtbacka, R. H. et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann. Surg. Oncol. 23, 4169–4177 (2016).
Bommareddy, P. K., Shettigar, M. & Kaufman, H. L. Integrating oncolytic viruses in combination cancer immunotherapy. Nat. Rev. Immunol. 18, 498–513 (2018).
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
Shrimali, R. K. et al. Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T cell apoptosis. Cancer Immunol. Res. 5, 755–766 (2017).
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Mlecnik, B. et al. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci. Transl Med. 6, 228–237 (2014).
Mlecnik, B. et al. Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44, 698–711 (2016).
Wrangle, J. M. et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 19, 694–704 (2018).
Charych, D. H. et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin. Cancer Res. 22, 680–690 (2016).
Chen, P. L. et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov. 6, 827–837 (2016).
Mariathasan, S. et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Nagy, J. A., Chang, S. H., Dvorak, A. M. & Dvorak, H. F. Why are tumour blood vessels abnormal and why is it important to know? Br. J. Cancer 100, 865–869 (2009).
Anderson, K. G., Stromnes, I. M. & Greenberg, P. D. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31, 311–325 (2017).
Slaney, C. Y., Kershaw, M. H. & Darcy, P. K. Trafficking of T cells into tumors. Cancer Res. 74, 7168–7174 (2014).
Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14, 28–36 (2008).
Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013).
Johansson-Percival, A. et al. Intratumoral LIGHT restores pericyte contractile properties and vessel integrity. Cell Rep. 13, 2687–2698 (2015).
Johansson-Percival, A. et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. Nat. Immunol. 18, 1207–1217 (2017).
Zhang, Y. et al. Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy. Proc. Natl Acad. Sci. USA 113, 4158–4163 (2016).
Chimote, A. A. et al. A defect in KCa3.1 channel activity limits the ability of CD8(+) T cells from cancer patients to infiltrate an adenosine-rich microenvironment. Sci. Signal. 11, eaaq1616 (2018).
Guirnalda, P., Wood, L., Goenka, R., Crespo, J. & Paterson, Y. Interferon gamma-induced intratumoral expression of CXCL9 alters the local distribution of T cells following immunotherapy with Listeria monocytogenes. Oncoimmunology 2, e25752 (2013).
Harlin, H. et al. Chemokine expression in melanoma metastases associated with CD8+ T cell recruitment. Cancer Res. 69, 3077–3085 (2009).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Tauriello, D. V. F. et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).
Mondino, A., Vella, G. & Icardi, L. Targeting the tumor and its associated stroma: one and one can make three in adoptive T cell therapy of solid tumors. Cytokine Growth Factor Rev. 36, 57–65 (2017).
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479 (2018).
Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 (2017).
Garcia-Martinez, E. et al. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. Breast Cancer Res. 16, 488 (2014).
Taniguchi, K. & Karin, M. NF-kappaB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18, 309–324 (2018).
Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668 (2017).
Ugel, S., De Sanctis, F., Mandruzzato, S. & Bronte, V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J. Clin. Invest. 125, 3365–3376 (2015).
Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).
Condamine, T., Ramachandran, I., Youn, J. I. & Gabrilovich, D. I. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu. Rev. Med. 66, 97–110 (2015).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Cook, J. & Hagemann, T. Tumour-associated macrophages and cancer. Curr. Opin. Pharmacol. 13, 595–601 (2013).
Zhang, Q. W. et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLOS ONE 7, e50946 (2012).
Fleming, V. et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front. Immunol. 9, 398 (2018).
Glodde, N. et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity 47, 789–802 (2017).
Eriksson, E., Wenthe, J., Irenaeus, S., Loskog, A. & Ullenhag, G. Gemcitabine reduces MDSCs, tregs and TGFbeta-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J. Transl Med. 14, 282 (2016).
Orillion, A. et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin. Cancer Res. 23, 5187–5201 (2017).
De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature 539, 443–447 (2016).
Calcinotto, A. et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 559, 363–369 (2018).
Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).
Su, Y. L., Banerjee, S., White, S. V. & Kortylewski, M. STAT3 in tumor-associated myeloid cells: multitasking to disrupt immunity. Int. J. Mol. Sci. 19, 1803 (2018).
Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).
Kortylewski, M. & Moreira, D. Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities. Cancer Immunol. Immunother. 66, 979–988 (2017).
Woods, D. M., Ramakrishnan, R., Sodré, A. L., Berglund, A. & Weber, J. PD-1 blockade induces phosphorylated STAT3 and results in an increase of Tregs with reduced suppressive function. J. Immunol. 198, 56.7 (2017).
Gopalakrishnan, V., Helmink, B. A., Spencer, C. N., Reuben, A. & Wargo, J. A. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33, 570–580 (2018).
Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).
Zitvogel, L., Ma, Y., Raoult, D., Kroemer, G. & Gajewski, T. F. The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science 359, 1366–1370 (2018).
Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).
Routy, B. et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 15, 382–396 (2018).
Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).
Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013).
Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).
Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).
Shono, Y. & van den Brink, M. R. M. Gut microbiota injury in allogeneic haematopoietic stem cell transplantation. Nat. Rev. Cancer 18, 283–295 (2018).
Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).
Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).
June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).
Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).
D’Aloia, M. M., Zizzari, I. G., Sacchetti, B., Pierelli, L.& Alimandi, M. CAR-T cells: the long and winding road to solid tumors. Cell Death Dis. 9, 282 (2018).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438 (2018).
Rupp, L. J. et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 737 (2017).
Kloss, C. C. et al. Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol. Ther. 26, 1855–1866 (2018).
Daher, M. & Rezvani, K. Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. Curr. Opin. Immunol. 51, 146–153 (2018).