Innate and adaptive immune cells in the tumor microenvironment

Nature Immunology - Tập 14 Số 10 - Trang 1014-1022 - 2013
Jesús García‐Foncillas1, Hans Schreiber2, Yang‐Xin Fu2
1#N# #N# University of Chicago, Chicago, Illinois, USA
2university of chicago, chicago, usa

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van der Bruggen, P. et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 (1991).

Topalian, S.L. et al. Recognition of shared melanoma antigens by human tumor-infiltrating lymphocytes. J. Immunother. 12, 203–206 (1992).

Monach, P.A., Meredith, S.C., Siegel, C.T. & Schreiber, H. A unique tumor antigen produced by a single amino acid substitution. Immunity 2, 45–59 (1995).

Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

Brichard, V.G. & Lejeune, D. GSK's antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development. Vaccine 25 (suppl. 2), B61–B71 (2007).

Boon, T., Gajewski, T.F. & Coulie, P.G. From defined human tumor antigens to effective immunization? Immunol. Today 16, 334–336 (1995).

Bos, R., Marquardt, K.L., Cheung, J. & Sherman, L.A. Functional differences between low- and high-affinity CD8+ T cells in the tumor environment. OncoImmunology 1, 1239–1247 (2012).

Engels, B. et al. Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell 23, 516–526 (2013).

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). This is the first study to define mutated antigens through exome sequencing as the major targets for tumor-infiltrating lymphocytes in human melanoma patients.

Nielsen, M. et al. NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS ONE 2, e796 (2007).

Pages, F. et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654–2666 (2005).

Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006). These data suggest that activated CD8+ T cells in the tumor microenvironment can have powerful prognostic importance in patients with colorectal cancer.

Mlecnik, B. et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J. Clin. Oncol. 29, 610–618 (2011).

Galon, J. et al. Cancer classification using the Immunoscore: a worldwide task force. J. Transl. Med. 10, 205 (2012).

Azimi, F. et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol. 30, 2678–2683 (2012).

Kreike, B. et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 9, R65 (2007).

Mahmoud, S.M. et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29, 1949–1955 (2011).

Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

Rusakiewicz, S. et al. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res. 73, 3499–3510 (2013).

Curiel, T.J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).

Bui, J.D. & Schreiber, R.D. Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr. Opin. Immunol. 19, 203–208 (2007).

Pufnock, J.S. & Rothstein, J.L. Oncoprotein signaling mediates tumor-specific inflammation and enhances tumor progression. J. Immunol. 182, 5498–5506 (2009).

Russell, J.P. et al. Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors. Oncogene 22, 4569–4577 (2003).

Harlin, H., Kuna, T.V., Peterson, A.C., Meng, Y. & Gajewski, T.F. Tumor progression despite massive influx of activated CD8+ T cells in a patient with malignant melanoma ascites. Cancer Immunol. Immunother. 55, 1185–1197 (2006).

Mortarini, R. et al. Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. Cancer Res. 63, 2535–2545 (2003).

Appay, V. et al. New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J. Immunol. 177, 1670–1678 (2006).

Rosenberg, S.A. & Dudley, M.E. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr. Opin. Immunol. 21, 233–240 (2009).

Gajewski, T.F. Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin. Cancer Res. 13, 5256–5261 (2007).

Spranger, S. et al. Upregulation of PD-L1, IDO and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. (in the press).

Chen, L. et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71, 1093–1102 (1992).

Brown, I.E., Blank, C., Kline, J., Kacha, A.K. & Gajewski, T.F. Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J. Immunol. 177, 4521–4529 (2006).

Zheng, Y. et al. Egr2-dependent gene expression profiling and ChIP-seq reveal novel biologic targets in T cell anergy. Mol. Immunol. 55, 283–291 (2013).

Fuertes, M.B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011). This study first described the requirement for host type I interferon signaling in the innate immune sensing of cancer as a bridge to a spontaneous adaptive immune response.

Fuertes, M.B., Woo, S.R., Burnett, B., Fu, Y.X. & Gajewski, T.F. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 34, 67–73 (2013).

Diamond, M.S. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208, 1989–2003 (2011).

Dunn, G.P. et al. A critical function for type I interferons in cancer immunoediting. Nat. Immunol. 6, 722–729 (2005).

Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

Gajewski, T.F., Fuertes, M.B. & Woo, S.R. Innate immune sensing of cancer: clues from an identified role for type I IFNs. Cancer Immunol. Immunother. 61, 1343–1347 (2012).

Barber, G.N. Cytoplasmic DNA innate immune pathways. Immunol. Rev. 243, 99–108 (2011).

Sancho, D. et al. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J. Clin. Invest. 118, 2098–2110 (2008).

Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009).

Zelenay, S. et al. The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J. Clin. Invest. 122, 1615–1627 (2012).

Ahrens, S. et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36, 635–645 (2012).

Wei, S. et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65, 5020–5026 (2005).

Lou, Y. et al. Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. J. Immunol. 178, 1534–1541 (2007).

Liu, C. et al. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J. Clin. Invest. 118, 1165–1175 (2008).

Demoulin, S., Herfs, M., Delvenne, P. & Hubert, P. Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms. J. Leukoc. Biol. 93, 343–352 (2013).

Sisirak, V. et al. Impaired IFN-alpha production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Cancer Res. 72, 5188–5197 (2012).

Chen, W., Liang, X., Peterson, A.J., Munn, D.H. & Blazar, B.R. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J. Immunol. 181, 5396–5404 (2008).

Watkins, S.K. et al. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. J. Clin. Invest. 121, 1361–1372 (2011).

Poulin, L.F. et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J. Exp. Med. 207, 1261–1271 (2010).

Poulin, L.F. et al. DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and non-lymphoid tissues. Blood 119, 6052–6062 (2012).

Messina, J.L. et al. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci Rep 2, 765 (2012).

Martinet, L. et al. High endothelial venules (HEVs) in human melanoma lesions: major gateways for tumor-infiltrating lymphocytes. OncoImmunology 1, 829–839 (2012).

Harlin, H. et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009). This study defined the two broad phenotypes of human melanoma, largely based on the presence or absence of T cell markers and chemokine transcripts.

Mortarini, R. et al. Constitutive expression and costimulatory function of LIGHT/TNFSF14 on human melanoma cells and melanoma-derived microvesicles. Cancer Res. 65, 3428–3436 (2005).

Yu, P. et al. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat. Immunol. 5, 141–149 (2004). This work demonstrated that introduction of the TNF superfamily member LIGHT into the tumor microenvironment could be sufficient to cause tumor rejection in vivo.

de Visser, K.E., Korets, L.V. & Coussens, L.M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).

Daniel, D. et al. Immune enhancement of skin carcinogenesis by CD4+ T cells. J. Exp. Med. 197, 1017–1028 (2003).

Shields, J.D., Kourtis, I.C., Tomei, A.A., Roberts, J.M. & Swartz, M.A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010).

Guerra, N. et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28, 571–580 (2008).

Mishra, R., Chen, A.T., Welsh, R.M. & Szomolanyi-Tsuda, E. NK cells and gammadelta T cells mediate resistance to polyomavirus-induced tumors. PLoS Pathog. 6, e1000924 (2010).

Smyth, M.J. et al. NKG2D function protects the host from tumor initiation. J. Exp. Med. 202, 583–588 (2005).

Fine, J.H. et al. Chemotherapy-induced genotoxic stress promotes sensitivity to natural killer cell cytotoxicity by enabling missing-self recognition. Cancer Res. 70, 7102–7113 (2010).

Jung, H., Hsiung, B., Pestal, K., Procyk, E. & Raulet, D.H. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J. Exp. Med. 209, 2409–2422 (2012).

Liu, R.B. et al. Densely granulated murine NK cells eradicate large solid tumors. Cancer Res. 72, 1964–1974 (2012).

Delahaye, N.F. et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat. Med. 17, 700–707 (2011).

Zhang, T., Lemoi, B.A. & Sentman, C.L. Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Blood 106, 1544–1551 (2005).

Barber, A., Rynda, A. & Sentman, C.L. Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J. Immunol. 183, 6939–6947 (2009).

Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734–738 (2002).

Jinushi, M., Hodi, F.S. & Dranoff, G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc. Natl. Acad. Sci. USA 103, 9190–9195 (2006).

Kabelitz, D., Wesch, D., Pitters, E. & Zoller, M. Characterization of tumor reactivity of human V gamma 9V delta 2 gamma delta T cells in vitro and in SCID mice in vivo. J. Immunol. 173, 6767–6776 (2004).

Mattarollo, S.R., Kenna, T., Nieda, M. & Nicol, A.J. Chemotherapy and zoledronate sensitize solid tumour cells to Vgamma9Vdelta2 T cell cytotoxicity. Cancer Immunol. Immunother. 56, 1285–1297 (2007).

Marcu-Malina, V. et al. Redirecting alphabeta T cells against cancer cells by transfer of a broadly tumor-reactive gammadeltaT-cell receptor. Blood 118, 50–59 (2011).

Di Carlo, E. et al. Mechanisms of the antitumor activity of human Vgamma9Vdelta2 T cells in combination with zoledronic acid in a preclinical model of neuroblastoma. Mol. Ther. 21, 1034–1043 (2013).

Kobayashi, H., Tanaka, Y., Yagi, J., Minato, N. & Tanabe, K. Phase I/II study of adoptive transfer of gammadelta T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma. Cancer Immunol. Immunother. 60, 1075–1084 (2011).

Peng, G. et al. Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity 27, 334–348 (2007).

Moreno, M. et al. IFN-gamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses. J. Immunol. 181, 2446–2454 (2008).

Swann, J.B. et al. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113, 6382–6385 (2009).

Paget, C., Chow, M.T., Duret, H., Mattarollo, S.R. & Smyth, M.J. Role of gammadelta T cells in alpha-galactosylceramide-mediated immunity. J. Immunol. 188, 3928–3939 (2012).

Terabe, M. et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat. Immunol. 1, 515–520 (2000).

Shimizu, K. et al. Vaccination with antigen-transfected, NKT cell ligand-loaded, human cells elicits robust in situ immune responses by dendritic cells. Cancer Res. 73, 62–73 (2013).

Richter, J. et al. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121, 423–430 (2013).

Singh, S., Ross, S.R., Acena, M., Rowley, D.A. & Schreiber, H. Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells. J. Exp. Med. 175, 139–146 (1992).

Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330, 827–830 (2010). This study revealed the critical role for FAP-expressing fibroblasts in tumor support and also in impeding antitumor immunity.

Wen, Y. et al. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci. 101, 2325–2332 (2010).

Edosada, C.Y. et al. Selective inhibition of fibroblast activation protein protease based on dipeptide substrate specificity. J. Biol. Chem. 281, 7437–7444 (2006).

Narra, K. et al. Phase II trial of single agent Val-boroPro (Talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer. Cancer Biol. Ther. 6, 1691–1699 (2007).

Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012).

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).

Mukai, S., Kagamu, H., Shu, S. & Plautz, G.E. Critical role of CD11a (LFA-1) in therapeutic efficacy of systemically transferred antitumor effector T cells. Cell. Immunol. 192, 122–132 (1999).

Strasly, M. et al. IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk. J. Immunol. 166, 3890–3899 (2001).

Johnson, L.A. et al. An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J. Exp. Med. 203, 2763–2777 (2006).

Dengel, L.T. et al. Interferons induce CXCR3-cognate chemokine production by human metastatic melanoma. J. Immunother. 33, 965–974 (2010).

Kunz, M. et al. Strong expression of the lymphoattractant C–X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma. J. Pathol. 189, 552–558 (1999).

Quatromoni, J.G. & Eruslanov, E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am. J. Transl. Res. 4, 376–389 (2012).

Rodriguez, P.C. et al. L-arginine consumption by macrophages modulates the expression of CD3zeta chain in T lymphocytes. J. Immunol. 171, 1232–1239 (2003).

Nagaraj, S. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13, 828–835 (2007).

Zhang, B. et al. Equilibrium between host and cancer caused by effector T cells killing tumor stroma. Cancer Res. 68, 1563–1571 (2008). This was the first study to demonstrate that immune system–mediated targeting of tumor stroma alone could control tumor growth in vivo.

Beatty, G.L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011). This work revealed a surprising mechanism of action of anti-CD40 monoclonal antibody in vivo , through macrophage-dependent remodeling of tumor stroma.

Brose, M.S. et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000 (2002).

Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

Flaherty, K.T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

Messina, J.L. et al. Activated stat-3 in melanoma. Cancer Control 15, 196–201 (2008).

Niu, G. et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21, 7001–7010 (2002).

Zhou, X.P. et al. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am. J. Pathol. 157, 1123–1128 (2000).

Massi, D. et al. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Mod. Pathol. 19, 246–254 (2006).

Larue, L. & Delmas, V. The WNT/Beta-catenin pathway in melanoma. Front. Biosci. 11, 733–742 (2006).

Delmas, V. et al. Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev. 21, 2923–2935 (2007).

Burdelya, L. et al. Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects. J. Immunol. 174, 3925–3931 (2005).

Ugurel, S. et al. Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol. Immunother. 57, 685–691 (2008).

Uccellini, L. et al. IRF5 gene polymorphisms in melanoma. J. Transl. Med. 10, 170 (2012).

Ivanov, I.I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

Wu, H.J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

Gajewski, T.F., Louahed, J. & Brichard, V.G. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16, 399–403 (2010). This paper summarized the early data suggesting, for the first time, that a T cell and chemokine-rich tumor microenvironment might define a predictive biomarker for response to immunotherapies, particularly vaccines.

Hamid, O. et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 9, 204 (2011).

Ji, R.R. et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 61, 1019–1031 (2012).

Sullivan, R.J. et al. A single center experience with high-dose IL-2 treatment for patients with advanced melanoma and pilot investigation of a novel gene expression signature as a predictor of response. J. Clin. Oncol. 27:15S, abstract 9003 (2009).

Brahmer, J.R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

Topalian, S.L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012). These first-in-man results of an anti–PD-1 monoclonal antibody revealed impressive clinical activity in patients with melanoma, lung cancer and kidney cancer.

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, 127ra137 (2012).

Liu, X. et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115, 3520–3530 (2010).

Rasku, M.A. et al. Transient T cell depletion causes regression of melanoma metastases. J. Transl. Med. 6, 12 (2008).

Telang, S. et al. Phase II trial of the regulatory T cell–depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma. BMC Cancer 11, 515 (2011).

Attia, P., Maker, A.V., Haworth, L.R., Rogers-Freezer, L. & Rosenberg, S.A. Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J. Immunother. 28, 582–592 (2005).

Rech, A.J. et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 4, 134ra162 (2012).

Boussiotis, V.A. et al. Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor. Science 266, 1039–1042 (1994).

Sportes, C. et al. Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin. Cancer Res. 16, 727–735 (2010).

Kim-Schulze, S., Kim, H.S., Fan, Q., Kim, D.W. & Kaufman, H.L. Local IL-21 promotes the therapeutic activity of effector T cells by decreasing regulatory T cells within the tumor microenvironment. Mol. Ther. 17, 380–388 (2009).

Petrella, T.M. et al. Interleukin-21 has activity in patients with metastatic melanoma: a phase II study. J. Clin. Oncol. 30, 3396–3401 (2012).

Tan, J.T. et al. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med. 195, 1523–1532 (2002).

Gattinoni, L. et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202, 907–912 (2005).

Kline, J. et al. Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. Clin. Cancer Res. 14, 3156–3167 (2008).

Woo, S.R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

Curran, M.A., Montalvo, W., Yagita, H. & Allison, J.P. 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. USA 107, 4275–4280 (2010).

Burnette, B., Fu, Y.X. & Weichselbaum, R.R. The confluence of radiotherapy and immunotherapy. Front. Oncol. 2, 143 (2012).

Yu, P. et al. Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastases. J. Immunol. 179, 1960–1968 (2007).

Burnette, B.C. et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 71, 2488–2496 (2011).

Rakhra, K. et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18, 485–498 (2010).

Balachandran, V.P. et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat. Med. 17, 1094–1100 (2011). This important study demonstrated that the therapeutic effect of the kinase inhibitor imatinib in the setting of GIST worked, in part, through an immunologic mechanism.

Frederick, D.T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).

Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007). This pivotal study demonstrated that host innate immune sensing through TLR signals had a critical role in the therapeutic effect of several chemotherapy drugs.

Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta–dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).

Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

Liang, H. et al. Radiation-induced equilibrium is a balance between tumor cell proliferation and T cell-mediated killing. J. Immunol. 190, 5874–5881 (2013).

Zeng, J. et al. Anti–PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int. J. Radiat. Oncol. Biol. Phys. 86, 343–349 (2013).