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The Immune Microenvironment of Human Tumors: General Significance and Clinical Impact

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Cancer Microenvironment

Abstract

Human cancers grow in a microenvironment of stromal, inflammatory and immunocompetent cells which is variable from tumor to tumor. The characterization of the immune contexture, i.e. the type, density and functional orientation of immunocompetent cells, the presence or absence of tertiary lymphoid structures is a major prognostic factor for patients survival and represent a guide and a target for innovative cancer therapies.

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References

  1. Coussens LM and Werb 2 (2002) Inflammation and Cancer. Nature 420:860–867

    Google Scholar 

  2. Hannahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  Google Scholar 

  3. Noman MZ, Messai Y, Carré T, Akalay I, Méron M, Janji B, Hasmim M, Chouaib S (2011) Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response. Crit Rev Immunol 31(5):357–377

    Article  PubMed  CAS  Google Scholar 

  4. Qin Z, Blankenstein T (2004) A cancer immunosurveillance controversy. Nat Immunol 5:3–4

    Article  PubMed  CAS  Google Scholar 

  5. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohmé I, Forsberg B, Eklund B, Fjeldborg O, Friedberg M, Frödin L et al (1995) Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer 60(2):183–189

    Article  PubMed  CAS  Google Scholar 

  6. Long HM, Taylor GS, Rickinson AB (2011) Immune defence against EBV and EBV-associated disease. Curr Opin Immunol 23:258–264

    Article  PubMed  CAS  Google Scholar 

  7. Fridman WH, Mlecnik B, Bindea G, Pagès F, Galon J (2011) Immunosurveillance in human non-viral cancers. Curr Opin Immunol 23:272–278

    Article  PubMed  CAS  Google Scholar 

  8. Burnet FM (1964) Immunological factors in the process of carcinogenesis. Br Med Bull 202:154–158

    Google Scholar 

  9. Thomas L (1982) On immunosurveillance in human cancer. Yale J Biol 55:329–333

    PubMed  CAS  Google Scholar 

  10. Dunn GP, Old LJ, Screiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  PubMed  CAS  Google Scholar 

  11. Koebel CM et al (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–907

    Article  PubMed  CAS  Google Scholar 

  12. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570

    Article  PubMed  CAS  Google Scholar 

  13. Mackie RM, Reid R, Junor B (2003) Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 348:567–568

    Article  PubMed  Google Scholar 

  14. Fridman WH, Pagès F, Sautès-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306

    Article  PubMed  CAS  Google Scholar 

  15. Pagès F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès-Fridman C, Fridman WH (2010) Immune infiltration in human tumors, a prognostic factor that should not be ignored. Oncogene 29(8):1093–1102

    Article  PubMed  Google Scholar 

  16. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Berger A, Camus M, Mlecnik B, Bruneval P, Molidor R, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predicts clinical outcome. Science 313:1960–1964

    Article  PubMed  CAS  Google Scholar 

  17. Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J (2009) In situ cytotoxic and memory T cells predict outcome in early-stage colorectal cancer patients. J Clin Oncol 27(35):5944–5951

    Article  PubMed  Google Scholar 

  18. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pages F, Galon J et al (2011) Histopathological-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 29(6):610–618

    Article  PubMed  Google Scholar 

  19. Katz SC, Pillarisetty V, Bamboat ZM et al (2009) T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol 16:2524–2530

    Article  PubMed  Google Scholar 

  20. Leffers N, Gooden MJ, de Jong RA et al (2009) Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58:449–459

    Article  PubMed  Google Scholar 

  21. Halama N, Michel S, Kloor M et al (2011) Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 71:5670–5677

    Article  PubMed  CAS  Google Scholar 

  22. Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  PubMed  CAS  Google Scholar 

  23. 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 (2012) Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    Article  PubMed  CAS  Google Scholar 

  24. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  PubMed  CAS  Google Scholar 

  25. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    Article  PubMed  CAS  Google Scholar 

  26. Mantovani A, Allavena P, Sica A, Balckwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  PubMed  CAS  Google Scholar 

  27. Sautès-Fridman C, Cherfils-Vicini J, Damotte D, Fisson S, Fridman WH, Cremer I, Dieu-Nosjean MC (2011) Tumor microenvironment is multifaceted. Cancer Metastasis Rev 30:13–25

    Article  PubMed  Google Scholar 

  28. Platonova S, Cherfils-Vicini J, Damotte D, Crozet L, Vieillard V, Validire P, André P, Dieu-Nosjean MC, Alifano M, Régnard JF, Fridman WH, Sautès-Fridman C, Cremer I (2011) Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res 71:5412–5422

    Article  PubMed  CAS  Google Scholar 

  29. Donskov F, von der Maase H (2006) Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol 24:1997–2005

    Article  PubMed  Google Scholar 

  30. Galon J, Fridman WH, Pagès F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886

    Article  PubMed  CAS  Google Scholar 

  31. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman WH, Cadranel J (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410–4417

    Article  PubMed  CAS  Google Scholar 

  32. Pagès 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 (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666

    Article  PubMed  Google Scholar 

  33. de Chaisemartin L, Goc J, Damotte D, Validire P, Magdeleinat P, Alifano M, Cremer I, Fridman WH, Sautès-Fridman C, Dieu-Nosjean MC (2011) Characterization of chemokines and adhesion moleucles associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res 71:6391–6399

    Article  PubMed  Google Scholar 

  34. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, Rochaix P, Girard JP (2011) Human solid tumors contain high endothelial venules: association with T-and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 71:5678–5687

    Article  PubMed  CAS  Google Scholar 

  35. Galon J, Pagès F, Marincola FM, Thurin M, Trinchieri G, Fox BA, Gajewski TF, Ascierto PA (2012) The immune score as a new possible approach for the classification of cancer. J Transl Med 10:1

    Article  PubMed  Google Scholar 

  36. Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, Camus M, Gillard M, Bruneval P, Fridman WH, Pagès F, Trajanoski Z, Galon J (2010) Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 138:1429–1440

    Article  PubMed  CAS  Google Scholar 

  37. Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480:480–489

    Article  PubMed  CAS  Google Scholar 

  38. Carragher DM, Rangel-Moreno J, Randall TD (2008) Ectopic lymphoid tissues and local immunity. Semin Immunol 20(1):26–42

    Article  PubMed  CAS  Google Scholar 

  39. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, Woodland DL, Lund FE, Randall TD (2004) Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10(9):927–934

    Article  PubMed  CAS  Google Scholar 

  40. Moyron-Quiroz JE, Rangel-Moreno J, Hartson L, Kusser K, Tighe MP, Klonowski KD, Lefrançois L, Cauley LS, Harmsen AG, Lund FE, Randall TD (2006) Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity 25(4):643–654

    Article  PubMed  CAS  Google Scholar 

  41. Fridman WH, Teillaud JL, Sautès-Fridman C, Pagès F, Galon J, Zucman-Rossi J, Tartour E, Zitvogel L, Kroemer G (2011) The ultimate goal of curative anti-cancer therapies: inducing an adaptive anti-tumor immune response. Front Immunol 2:66

    PubMed  Google Scholar 

  42. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136

    PubMed  CAS  Google Scholar 

  43. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593

    Article  PubMed  Google Scholar 

  44. de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411–423

    Article  PubMed  Google Scholar 

  45. Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S, Korets L, Lam J, Tawfik D, DeNardo DG, Naldini L, de Visser KE, De Palma M, Coussens LM (2010) FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17:121–134

    Article  PubMed  CAS  Google Scholar 

  46. Qin Z, Richter G, Schüler T, Ibe S, Cao X, Blankenstein T (1998) B cells inhibit induction of T cell-dependent tumor immunity. Nat Med 4(5):627–630

    Article  PubMed  CAS  Google Scholar 

  47. Kim S, Fridlender ZG, Dunn R, Kehry MR, Kapoor V, Blouin A, Kaiser LR, Albelda SM (2008) B-cell depletion using an anti-CD20 antibody augments antitumor immune responses and immunotherapy in nonhematopoetic murine tumor models. J Immunother 31(5):446–457

    Article  PubMed  CAS  Google Scholar 

  48. Menegaz RA, Michelin MA, Etchebehere RM, Fernandes PC, Murta EF (2008) Peri and intratumoral T and B lymphocytic infiltration in breast cancer. Eur J Gynaecol Oncol 29:321–326

    PubMed  CAS  Google Scholar 

  49. Simsa P, Teillaud JL, Stott DI, Tóth J, Kotlan B (2005) Tumor-infiltrating B cell immunoglobulin variable region gene usage in invasive ductal breast carcinoma. Pathol Oncol Res 11(2):92–97

    Article  CAS  Google Scholar 

  50. Kotlan B, Simsa P, Teillaud JL, Fridman WH, Toth J, McKnight M, Glassy MC (2005) Novel ganglioside antigen identified by B cells in human medullary breast carcinomas: the proof of principle concerning the tumor-infiltrating B lymphocytes. J Immunol 175(4):2278–2285

    PubMed  CAS  Google Scholar 

  51. Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Gonçalves A, André P, Romagné F, Thibault G, Viens P, Birnbaum D, Bertucci F, Moretta A, Olive D (2011) Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest 121:3609–3622

    Article  PubMed  CAS  Google Scholar 

  52. Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pagès F, Galon J (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71:1263–1271

    Article  PubMed  CAS  Google Scholar 

  53. Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160

    Article  PubMed  CAS  Google Scholar 

  54. Nardin A, Wong WC, Tow C, Molina TJ, Tissier F, Audebourg A, Garcette M, Caignard A, Avril MF, Abastado JP, Prévost-Blondel A (2011) Dacarbazine promotes stromal remodeling and lymphocyte infiltration in cutaneous melanoma lesions. J Invest Dermatol 131:1896–1905

    Article  PubMed  CAS  Google Scholar 

  55. Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, Kefford RF, Hersey P, Scolyer RA (2011) Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 18:1386–1394

    Article  PubMed  Google Scholar 

  56. Adotevi O, Pere H, Ravel P, Haicheur N, Badoual C, Merillon N, Medioni J, Peyrard S, Roncelin S, Verkarre V, Mejean A, Fridman WH, Oudard S, Tartour E (2010) A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 33:991–998

    Article  PubMed  CAS  Google Scholar 

  57. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434

    Article  PubMed  CAS  Google Scholar 

  58. Rosenblatt J, Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD, Joyce RM, Wellenstein K, Keefe W, Schickler M, Rotem-Yehudar R, Kufe D, Avigan D (2011) PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 34:409–418

    Article  PubMed  CAS  Google Scholar 

  59. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y (2007) Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 13:2151–2157

    Article  PubMed  CAS  Google Scholar 

  60. Jass JR (1986) Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 39:585–589

    Article  PubMed  CAS  Google Scholar 

  61. Tartour E, Fossiez F, Joyeux I, Galinha A, Gey A, Claret E, Sastre-Garau X, Couturier J, Mosseri V, Vives V, Banchereau J, Fridman WH, Wijdenes J, Lebecque S, Sautès-Fridman C (1999) Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res 59:3698–3704

    PubMed  CAS  Google Scholar 

  62. Tartour E, Gey A, Sastre-Garau X, Lombard Surin I, Mosseri V, Fridman WH (1998) Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas. J Natl Cancer Inst 90:287–294

    Article  PubMed  CAS  Google Scholar 

  63. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213

    Article  PubMed  CAS  Google Scholar 

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Financial support

This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Descartes, Université Pierre et Marie Curie, Labex Immuno-oncologie, Institut National du Cancer and Cancéropole Ile-de-France, (2011-1-PLBIO-06-INSERM 6-1, PLBIO09-088-IDF-KROEMER, 11LAXE62_9UMS872 FRIDMAN); Legs Poix and the Association pour la Recherche sur le Cancer, ARC, 2009, 3185 and Fondation pour la Recherche Médicale (FRM).

Grant support

The work was supported by the «Institut National de la Santé et de la Recherche Médicale», the «Université Paris-Descartes Paris 5», the «Association pour la Recherche sur le Cancer» (grant n°421: RPT07002DDP), and the «Cancéropole Ile-de-France» (grants n°: RPT09004DDA and RPT10007DDA).

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U872, Centre de Recherche des Cordeliers, 15 rue de l’Ecole de Médecine, 75006, Paris, France

    Wolf-Herman Fridman, Marie-Caroline Dieu-Nosjean, Franck Pagès, Isabelle Cremer, Diane Damotte, Catherine Sautès-Fridman & Jérôme Galon

  2. Université Pierre et Marie Curie-Paris 6, UMRS 872, Paris, France

    Wolf-Herman Fridman, Marie-Caroline Dieu-Nosjean, Franck Pagès, Isabelle Cremer, Diane Damotte, Catherine Sautès-Fridman & Jérôme Galon

  3. Université Paris Descartes-Paris 5, UMRS 872, Paris, France

    Wolf-Herman Fridman, Marie-Caroline Dieu-Nosjean, Franck Pagès, Isabelle Cremer, Diane Damotte, Catherine Sautès-Fridman & Jérôme Galon

  4. Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Wolf-Herman Fridman & Franck Pagès

  5. Services d’anatomie-pathologique et de chirurgie thoracique, Hôpital Hôtel Dieu, AP-HP, Paris, France

    Diane Damotte

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  1. Wolf-Herman Fridman
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  2. Marie-Caroline Dieu-Nosjean
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Correspondence to Wolf-Herman Fridman.

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Fridman, WH., Dieu-Nosjean, MC., Pagès, F. et al. The Immune Microenvironment of Human Tumors: General Significance and Clinical Impact. Cancer Microenvironment 6, 117–122 (2013). https://doi.org/10.1007/s12307-012-0124-9

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