Skip to main content

Advertisement

SpringerLink
Log in

Shaping of an effective immune microenvironment to and by cancer cells

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

A high density of intratumoral effector memory CD8+/Th1 T cells is associated with favorable prognosis in most cancers and may be induced or increased by immunotherapy. Efficient adaptive immune reactions are shaped in tumor adjacent tertiary lymphoid structures, which exhibit all characteristics of immunity generating lymphoid formations in reactive lymph nodes. Malignant tumor cells impact favorably or deleteriously their immune microenvironment if they bear genetic mutations that result in neo-antigens or by producing chemokines and cytokines that recruit lymphocytes and myeloid cells or increase inflammation and neo-angiogenesis. This intricate network of interactions results in control or escape of tumors, and its understanding will help define goals to monitor efficiency of immunotherapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AID:

Activation-induced cytidine deaminase

CAR:

Chimeric antigen receptor

CIN:

Cervical intraepithelial neoplasia

CT:

Core tumor

DC:

Dendritic cell

HPV:

Human papilloma virus

IM:

Invasive margin

MDSC:

Myeloid-derived suppressor cell

MSI:

Microsatellite instability

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PFS:

Progression-free survival

SLO:

Secondary lymphoid organ

Ti-BALT:

Tumor-induced bronchus-associated lymphoid tissue

TIL:

Tumor-infiltrating leukocyte

TLS:

Tertiary lymphoid structure

Treg cell:

Regulatory T cell

References

  1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJM, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Brahmer JR, Tykodi SS, Chow LQM, Hwu W, 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-l1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. 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  PubMed Central  Google Scholar 

  4. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon R, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133

    Article  PubMed  CAS  Google Scholar 

  5. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified t cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. 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 

  7. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, Bruneval P, Fridman WH, Becker C, Pagès F, Speicher MR, Trajanoski Z, Galon J (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39:782–795

    Article  PubMed  CAS  Google Scholar 

  8. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc P, Trajanoski Z, Fridman W, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, Zlobec I, Berger A, Bifulco C, Botti G, Tatangelo F, Britten CM, Kreiter S, Chouchane L, Delrio P, Arndt H, Asslaber M, Maio M, Masucci GV, Mihm M, Vidal-Vanaclocha F, Allison JP, Gnjatic S, Hakansson L, Huber C, Singh-Jasuja H, Ottensmeier C, Zwierzina H, Laghi L, Grizzi F, Ohashi PS, Shaw PA, Clarke BA, Wouters BG, Kawakami Y, Hazama S, Okuno K, Wang E, O’Donnell-Tormey J, Lagorce C, Pawelec G, Nishimura MI, Hawkins R, Lapointe R, Lundqvist A, Khleif SN, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Palmqvist R, Nagtegaal ID, Wang Y, D’Arrigo C, Kopetz S, Sinicrope FA, Trinchieri G, Gajewski TF, Ascierto PA, Fox BA (2012) Cancer classification using the immunoscore: a worldwide task force. J Transl Med 10:205

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  12. Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape. Curr Opin Immunol 27:16–25

    Article  PubMed  CAS  Google Scholar 

  13. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LAJ, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. 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 

  15. Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B, Ben-Neriah S, Boyle M, Kridel R, Telenius A, Woolcock BW, Farinha P, Fisher RI, Rimsza LM, Bartlett NL, Cheson BD, Shepherd LE, Advani RH, Connors JM, Kahl BS, Gordon LI, Horning SJ, Steidl C, Gascoyne RD (2013) Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical hodgkin lymphoma. J Clin Oncol 31:692–700

    Article  PubMed  PubMed Central  Google Scholar 

  16. Whelchel JC, Farah SE, McLean IW, Burnier MN (1993) Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci 34:2603–2606

    PubMed  CAS  Google Scholar 

  17. Motz GT, Coukos G (2011) The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol 11:702–711

    Article  PubMed  CAS  Google Scholar 

  18. Terme M, Colussi O, Marcheteau E, Tanchot C, Tartour E, Taieb J (2012) Modulation of immunity by antiangiogenic molecules in cancer. Clin Dev Immunol 2012:492920

    Article  PubMed  PubMed Central  Google Scholar 

  19. Giraldo NA, Becht E, Remark R, Damotte D, Sautès-Fridman C, Fridman WH (2014) The immune contexture of primary and metastatic human tumours. Curr Opin Immunol 27:8–15

    Article  PubMed  CAS  Google Scholar 

  20. Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, Mauri C, Coussens LM, Balkwill FR (2011) B regulatory cells and the tumor-promoting actions of tnf-α during squamous carcinogenesis. Proc Natl Acad Sci USA 108:10662–10667

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Germain C, Gnjatic S, Tamzalit F, Knockaert S, Remark R, Goc J, Lepelley A, Becht E, Katsahian S, Bizouard G, Validire P, Damotte D, Alifano M, Magdeleinat P, Cremer I, Teillaud J, Fridman W, Sautès-Fridman C, Dieu-Nosjean M (2014) Presence of b cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am J Respir Crit Care Med 189:832–844

    Article  PubMed  CAS  Google Scholar 

  22. Ladányi A, Kiss J, Mohos A, Somlai B, Liszkay G, Gilde K, Fejös Z, Gaudi I, Dobos J, Tímár J (2011) Prognostic impact of b-cell density in cutaneous melanoma. Cancer Immunol Immunother 60:1729–1738

    Article  PubMed  Google Scholar 

  23. Mahmoud SMA, Lee AHS, Paish EC, Macmillan RD, Ellis IO, Green AR (2012) The prognostic significance of b lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 132:545–553

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. 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 P, Trajanoski Z, Fridman W, 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 

  26. 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 25:643–654

    Article  PubMed  CAS  Google Scholar 

  27. Martinet L, Le Guellec S, Filleron T, Lamant L, Meyer N, Rochaix P, Garrido I, Girard J (2012) High endothelial venules (hevs) in human melanoma lesions: major gateways for tumor-infiltrating lymphocytes. Oncoimmunology 1:829–839

    Article  PubMed  PubMed Central  Google Scholar 

  28. Dieu-Nosjean MC, Massacrier C, Homey B, Vanbervliet B, Pin JJ, Vicari A, Lebecque S, Dezutter-Dambuyant C, Schmitt D, Zlotnik A, Caux C (2000) Macrophage inflammatory protein 3alpha is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J Exp Med 192:705–718

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Thaunat O, Patey N, Caligiuri G, Gautreau C, Mamani-Matsuda M, Mekki Y, Dieu-Nosjean M, Eberl G, Ecochard R, Michel J, Graff-Dubois S, Nicoletti A (2010) Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol 185:717–728

    Article  PubMed  CAS  Google Scholar 

  30. Manzo A, Bombardieri M, Humby F, Pitzalis C (2010) Secondary and ectopic lymphoid tissue responses in rheumatoid arthritis: from inflammation to autoimmunity and tissue damage/remodeling. Immunol Rev 233:267–285

    Article  PubMed  CAS  Google Scholar 

  31. Neyt K, Perros F, GeurtsvanKessel CH, Hammad H, Lambrecht BN (2012) Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol 33:297–305

    Article  PubMed  CAS  Google Scholar 

  32. Dieu-Nosjean M, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman W, 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 

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

    Article  PubMed  Google Scholar 

  34. Goc J, Germain C, Vo-Bourgais TKD, Lupo A, Klein C, Knockaert S, de Chaisemartin L, Ouakrim H, Becht E, Alifano M, Validire P, Remark R, Hammond SA, Cremer I, Damotte D, Fridman W, Sautès-Fridman C, Dieu-Nosjean M (2014) Dendritic cells in tumor-associated tertiary lymphoid structures signal a th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating cd8+ t cells. Cancer Res 74:705–715

    Article  PubMed  CAS  Google Scholar 

  35. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie J, Rochaix P, Girard J (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 

  36. Dieu-Nosjean M, Goc J, Giraldo-Castillo N, Sautès-Fridman C, Fridman W (2014) Tertiary lymphoid structures in cancer and beyond (submitted)

  37. Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, Ravoet M, Le Buanec H, Sibille C, Manfouo-Foutsop G, Veys I, Haibe-Kains B, Singhal SK, Michiels S, Rothé F, Salgado R, Duvillier H, Ignatiadis M, Desmedt C, Bron D, Larsimont D, Piccart M, Sotiriou C, Willard-Gallo K (2013) Cd4+ follicular helper t cell infiltration predicts breast cancer survival. J Clin Invest 123:2873–2892

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Maldonado L, Teague JE, Morrow MP, Jotova I, Wu TC, Wang C, Desmarais C, Boyer JD, Tycko B, Robins HS, Clark RA, Trimble CL (2014) Intramuscular therapeutic vaccination targeting hpv16 induces t cell responses that localize in mucosal lesions. Sci Transl Med 6:221ra13

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bower M, Palmieri C, Dhillon T (2006) Aids-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis 19:14–19

    Article  PubMed  Google Scholar 

  40. 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 60:183–189

    Article  PubMed  CAS  Google Scholar 

  41. Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen Y, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD (2012) Cancer exome analysis reveals a t-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404

    Article  PubMed  CAS  Google Scholar 

  42. Remark R, Alifano M, Cremer I, Lupo A, Dieu-Nosjean M, Riquet M, Crozet L, Ouakrim H, Goc J, Cazes A, Fléjou J, Gibault L, Verkarre V, Régnard J, Pagès O, Oudard S, Mlecnik B, Sautès-Fridman C, Fridman W, Damotte D (2013) Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin. Clin Cancer Res 19:4079–4091

    Article  PubMed  CAS  Google Scholar 

  43. Marisa L, de Reyniès A, Duval A, Selves J, Gaub MP, Vescovo L, Etienne-Grimaldi M, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Fléjou J, Benchimol D, Berger A, Lagarde A, Pencreach E, Piard F, Elias D, Parc Y, Olschwang S, Milano G, Laurent-Puig P, Boige V (2013) Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 10:e1001453

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Mlecnik B, Bindea G, Angell HK, Sasso MS, Obenauf AC, Fredriksen T, Lafontaine L, Bilocq AM, Kirilovsky A, Tosolini M, Waldner M, Berger A, Fridman WH, Rafii A, Valge-Archer V, Pagès F, Speicher MR, Galon J (2014) Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci Transl Med 6:228ra37

    Article  PubMed  Google Scholar 

  45. Beuselinck B, Job S, Becht E, Karadimou A, Verkarre V, Couchy B, Giraldo-Castillo N, Rioux-Leclercq N, Molinié V, Sibony M, Elaidi R, Teghom C, Patard J, Fridman W, Sautès-Fridman C, de Reyniès A, Oudard S & Zucman-Rossi J (2014) Molecular subtypes of clear cell renal cell carcinoma are predictive of sunitinib response in the metastatic setting. Clin Cancer Res (in press)

Download references

Acknowledgments

We wish to thank Marco Alifano, Luc de Chaisemartin Diane Damotte, Samantha Knockaert, Laetitia Lacroix, Audrey Lupo, Hanane Ouakrim, Romain Remark and Pierre Validire for their active participation to the studies and Pierre Laurent-Puig, Aurelien de Reyniès, Benoit Beuselinck and Jessica Zucman-Rossi for their numerous and exciting discussions. This work was supported by Institut National de la Santé er de la Recherche Médicale (INSERM), University Paris Descartes, University Pierre et Marie Curie, SIRIC Cancer Research and Personalized Medicine (CARPEM), the LabeX Immuno-oncology, Institut National du Cancer and Canceropole Ile de France (2011-1-PLBIO-06-INSERM 6-1, PLBIO09-088-IDF-KROEMER, 11LAXE62_9UMS872 FRIDMAN).

Conflict of interest

Wolf-Herman Fridman received honorarium from Laboratoire du Fractionnement et des Biotechnologies (LFB), Pierre Fabre Medicament and Sanofi. The other authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory Cancer, Immune Control and Escape, UMRS 1138 INSERM, Cordeliers Research Center, 15, rue de l’école de Médecine, 75270, Paris Cedex 06, France

    Etienne Becht, Jeremy Goc, Claire Germain, Nicolas A. Giraldo, Marie-Caroline Dieu-Nosjean, Catherine Sautès-Fridman & Wolf-Herman Fridman

  2. Université Paris Descartes, Paris, France

    Etienne Becht, Jeremy Goc, Claire Germain, Nicolas A. Giraldo, Marie-Caroline Dieu-Nosjean, Catherine Sautès-Fridman & Wolf-Herman Fridman

  3. Université Pierre et Marie Curie, Paris, France

    Etienne Becht, Jeremy Goc, Claire Germain, Nicolas A. Giraldo, Marie-Caroline Dieu-Nosjean, Catherine Sautès-Fridman & Wolf-Herman Fridman

Authors
  1. Etienne Becht
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremy Goc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claire Germain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicolas A. Giraldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie-Caroline Dieu-Nosjean
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Catherine Sautès-Fridman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wolf-Herman Fridman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wolf-Herman Fridman.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Becht, E., Goc, J., Germain, C. et al. Shaping of an effective immune microenvironment to and by cancer cells. Cancer Immunol Immunother 63, 991–997 (2014). https://doi.org/10.1007/s00262-014-1590-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1590-3

Keywords

Search

Navigation