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Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment

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Tumor Immune Microenvironment in Cancer Progression and Cancer Therapy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1036))

Abstract

Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically evident nonetheless implies that immune escape must occur. Two major subsets of human melanoma metastases have been identified based on gene expression profiling. One subgroup has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and has been designated as non-T cell-inflamed. The mechanisms of immune escape are likely distinct in these two phenotypes, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, FoxP3+ Tregs, and evidence for T cell-intrinsic anergy. Therapeutic strategies to overcome these inhibitory mechanisms are being pursued, and anti-PD-1 mAbs have been FDA approved. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous, several of which are in clinical testing. A new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8α+ DCs. New strategies are being developed to engage this pathway therapeutically, such as through STING agonists. The molecular mechanisms that mediate the presence or absence of the T cell-inflamed tumor microenvironment are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway, suggesting that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment.

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References

  1. Peterson AC, Harlin H, Gajewski TF. Immunization with melan-A peptide-pulsed peripheral blood mononuclear cells plus recombinant human interleukin-12 induces clinical activity and T-cell responses in advanced melanoma. J Clin Oncol. 2003;21:2342–8.

    Article  CAS  PubMed  Google Scholar 

  2. Gajewski TF, Meng Y, Blank C, Brown I, Kacha A, Kline J, Harlin H. Immune resistance orchestrated by the tumor microenvironment. Immunol Rev. 2006;213:131–45.

    Article  CAS  PubMed  Google Scholar 

  3. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69:3077–85.

    Article  CAS  PubMed  Google Scholar 

  4. Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 2010;16:399–403.

    Article  CAS  PubMed  Google Scholar 

  5. Ulloa-Montoya F, Louahed J, Dizier B, Gruselle O, Spiessens B, Lehmann FF, Suciu S, Kruit WH, Eggermont AM, Vansteenkiste J, Brichard VG. Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. J Clin Oncol. 2013;31:2388–95.

    Article  CAS  PubMed  Google Scholar 

  6. Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, Ku AW, Frelinger JG, Odunsi K, Gajewski TF, Luster AD, Evans SS. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun. 2015;6:7458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66.

    Article  CAS  PubMed  Google Scholar 

  8. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  CAS  PubMed  Google Scholar 

  9. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pages F, Galon J. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29:610–8.

    Article  PubMed  Google Scholar 

  10. Harlin H, Kuna TV, Peterson AC, Meng Y, Gajewski TF. Tumor progression despite massive influx of activated CD8(+) T cells in a patient with malignant melanoma ascites. Cancer Immunol Immunother. 2006;55:1185–97.

    Article  CAS  PubMed  Google Scholar 

  11. Mortarini R, Piris A, Maurichi A, Molla A, Bersani I, Bono A, Bartoli C, Santinami M, Lombardo C, Ravagnani F, Cascinelli N, Parmiani G, Anichini A. 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. 2003;63:2535–45.

    CAS  PubMed  Google Scholar 

  12. Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, Rimoldi D, Guillaume P, Meidenbauer N, Mackensen A, Rufer N, Lubenow N, Speiser D, Cerottini JC, Romero P, Pittet MJ. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 2004;64:2865–73.

    Article  CAS  PubMed  Google Scholar 

  13. Rosenberg SA, Dudley ME. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14639–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol. 2010;17:718–30.

    Article  PubMed  Google Scholar 

  15. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827–30.

    Article  CAS  PubMed  Google Scholar 

  16. Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, Validire P, Trautmann A, Mami-Chouaib F, Donnadieu E. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest. 2012;122:899–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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. 2013;93:343–52.

    Article  CAS  PubMed  Google Scholar 

  18. Watkins SK, Zhu Z, Riboldi E, Shafer-Weaver KA, Stagliano KE, Sklavos MM, Ambs S, Yagita H, Hurwitz AA. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. J Clin Invest. 2011;121:1361–72.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, Katsaros D, O’Brien-Jenkins A, Gimotty PA, Coukos G. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med. 2008;14:28–36.

    Article  CAS  PubMed  Google Scholar 

  20. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gajewski TF, Zha Y-y, Hernandez K, Li Y, Bao R, Alexieff P, Andrade J, Luke JJ, Spranger S. Density of immunogenic antigens and presence or absence of the T cell-inflamed tumor microenvironment in metastatic melanoma|. J Clin Oncol. 2015;33(suppl; abstr):3002.

    Google Scholar 

  22. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–3.

    Article  CAS  PubMed  Google Scholar 

  23. Gajewski TF. Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin Cancer Res. 2007;13:5256–61.

    Article  CAS  PubMed  Google Scholar 

  24. Spranger S, Spaapen R, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Upregulation of PD-L1, IDO and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med. 2013;5(200):200ra116.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra137.

    Article  Google Scholar 

  26. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zheng Y, Zha Y, Driessens G, Locke F, Gajewski TF. Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo. J Exp Med. 2012;209:2157–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zheng Y, Zha Y, Gajewski TF. Molecular regulation of T-cell anergy. EMBO Rep. 2008;9:50–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zheng Y, Zha Y, Spaapen RM, Mathew R, Barr K, Bendelac A, Gajewski TF. Egr2-dependent gene expression profiling and ChIP-Seq reveal novel biologic targets in T cell anergy. Mol Immunol. 2013;55:283–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405.

    Article  CAS  PubMed  Google Scholar 

  33. Shuford WW, Klussman K, Tritchler DD, Loo DT, Chalupny J, Siadak AW, Brown TJ, Emswiler J, Raecho H, Larsen CP, Pearson TC, Ledbetter JA, Aruffo A, Mittler RS. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J Exp Med. 1997;186:47–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.

    Article  PubMed  Google Scholar 

  35. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987–95.

    Article  CAS  PubMed  Google Scholar 

  36. Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, Gajewski TF. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med. 2011;208(10):2005–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, Calderon B, Schraml BU, Unanue ER, Diamond MS, Schreiber RD, Murphy TL, Murphy KM. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science. 2008;322:1097–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, Lee H, Arthur CD, White JM, Kalinke U, Murphy KM, Schreiber RD. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. 2011;208:1989–2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fuertes MB, Woo SR, Burnett B, Fu YX, Gajewski TF. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 2013;34:67–73.

    Article  CAS  PubMed  Google Scholar 

  40. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339:786–91.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang X, Shi H, Wu J, Sun L, Chen C, Chen ZJ. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell. 2013;51:226–35.

    Article  CAS  PubMed  Google Scholar 

  43. Ahn J, Gutman D, Saijo S, Barber GN. STING manifests self DNA-dependent inflammatory disease. Proc Natl Acad Sci U S A. 2012;109:19386–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ahn J, Ruiz P, Barber GN. Intrinsic self-DNA triggers inflammatory disease dependent on STING. J Immunol. 2014;193:4634–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CC, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Woo S-R, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MYK, Duggan R, Wang Y, Barber GN, Fitzgerald KA, Alegre M-L, Gajewski TF. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41:830–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5:5166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M, David M, Watkins SC, Sarkar SN, Okada H. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res. 2014;2(12):1199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu Q, Man SM, Gurung P, Liu Z, Vogel P, Lamkanfi M, Kanneganti TD. Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J Immunol. 2014;193:4779–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Baguley BC, Ching LM. Immunomodulatory actions of xanthenone anticancer agents. BioDrugs. 1997;8:119–27.

    Article  CAS  PubMed  Google Scholar 

  51. Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, Losonczy G, Reck M, Heo DS, Fan X, Fandi A, Scagliotti G. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:2965–71.

    Article  CAS  PubMed  Google Scholar 

  52. Conlon J, Burdette DL, Sharma S, Bhat N, Thompson M, Jiang Z, Rathinam VA, Monks B, Jin T, Xiao TS, Vogel SN, Vance RE, Fitzgerald KA. Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J Immunol. 2013;190:5216–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gao P, Ascano M, Zillinger T, Wang W, Dai P, Serganov AA, Gaffney BL, Shuman S, Jones RA, Deng L, Hartmann G, Barchet W, Tuschl T, Patel DJ. Structure-function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell. 2013;154:748–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, Woo SR, Lemmens E, Banda T, Leong JJ, Metchette K, Dubensky TW Jr, Gajewski TF. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11:1018–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 2011;71:2488–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li X-D, Mauceri H, Beckett M, Darga T, Huang X, Gajewski TF, Chen ZJ, Fu Y-X, Weichselbaum RR. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.

    Article  CAS  PubMed  Google Scholar 

  58. Ugurel S, Schrama D, Keller G, Schadendorf D, Brocker EB, Houben R, Zapatka M, Fink W, Kaufman HL, Becker JC. Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol Immunother. 2008;57:685–91.

    Article  CAS  PubMed  Google Scholar 

  59. Uccellini L, De Giorgi V, Zhao Y, Tumaini B, Erdenebileg N, Dudley ME, Tomei S, Bedognetti D, Ascierto ML, Liu Q, Simon R, Kottyan L, Kaufman KM, Harley JB, Wang E, Rosenberg SA, Marincola FM. IRF5 gene polymorphisms in melanoma. J Transl Med. 2012;10:170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kariuki SN, Franek BS, Kumar AA, Arrington J, Mikolaitis RA, Utset TO, Jolly M, Crow MK, Skol AD, Niewold TB. Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. Arthritis Res Ther. 2010;12:R151.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, Dai RM, Kiu H, Cardone M, Naik S, Patri AK, Wang E, Marincola FM, Frank KM, Belkaid Y, Trinchieri G, Goldszmid RS. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342:967–70.

    Article  CAS  PubMed  Google Scholar 

  62. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Berard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Dore J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342:971–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. University of Chicago, Chicago, IL, USA

    Thomas F. Gajewski, Leticia Corrales, Jason Williams, Brendan Horton, Ayelet Sivan & Stefani Spranger

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  1. Thomas F. Gajewski
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  2. Leticia Corrales
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Correspondence to Thomas F. Gajewski .

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  1. Department of Medicine and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York, USA

    Pawel Kalinski

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Gajewski, T.F., Corrales, L., Williams, J., Horton, B., Sivan, A., Spranger, S. (2017). Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment. In: Kalinski, P. (eds) Tumor Immune Microenvironment in Cancer Progression and Cancer Therapy. Advances in Experimental Medicine and Biology, vol 1036. Springer, Cham. https://doi.org/10.1007/978-3-319-67577-0_2

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