Cancer Immunology, Immunotherapy

, Volume 61, Issue 6, pp 751–759

Tumor microenvironment and lymphocyte infiltration

Review

Abstract

There is ample evidence that the presence of tumor-infiltrating T lymphocytes is associated with a favorable prognostic in patients. These observations suggest that a limiting step to immune resistance and immunotherapy could be the capacity of tumor-specific T cells to reach tumor bed. In this article, we review some factors that may influence this infiltration, and in particular the nature of the vasculature, the expression of chemokines or tumor antigens and the presence of dendritic cells and CD4+ T lymphocytes.

Keywords

Tumor microenvironment Tumor-infiltrating lymphocytes (TIL) Vasculature Chemokines 

References

  1. 1.
    Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494PubMedGoogle Scholar
  2. 2.
    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-H, Trajanoski Z, Fridman W-H, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666PubMedCrossRefGoogle Scholar
  3. 3.
    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-H, Trajanoski Z, Fridman W-H, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (New York, N.Y.) 313:1960–1964Google Scholar
  4. 4.
    Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt J, Giovannucci E, Dranoff G, Fuchs CS, Ogino S (2010) Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 222:350–366PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty P, 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 348:203–213PubMedCrossRefGoogle Scholar
  6. 6.
    Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen Y, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Nat Acad Sci USA 102:18538–18543PubMedCrossRefGoogle Scholar
  7. 7.
    Bogunovic D, O’Neill DW, Belitskaya-Levy I, Vacic V, Yu Y, Adams S, Darvishian F, Berman R, Shapiro R, Pavlick AC, Lonardi S, Zavadil J, Osman I, Bhardwaj N (2009) Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proc Nat Acad Sci USA 106:20429–20434PubMedCrossRefGoogle Scholar
  8. 8.
    Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF (2009) Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 69:3077–3085PubMedCrossRefGoogle Scholar
  9. 9.
    Ferradini L, Mackensen A, Genevée C, Bosq J, Duvillard P, Avril MF, Hercend T (1993) Analysis of T cell receptor variability in tumor-infiltrating lymphocytes from a human regressive melanoma. Evidence for in situ T cell clonal expansion. J Clin Investig 91:1183–1190PubMedCrossRefGoogle Scholar
  10. 10.
    Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Törne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113PubMedCrossRefGoogle Scholar
  11. 11.
    Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, Mariani G, Rodriguez J, Carcangiu M, Watson D, Valagussa P, Rouzier R, Symmans WF, Ross JS, Hortobagyi GN, Pusztai L, Shak S (2005) Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 23:7265–7277PubMedCrossRefGoogle Scholar
  12. 12.
    Hornychova H, Melichar B, Tomsova M, Mergancova J, Urminska H, Ryska A (2008) Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest 26:1024–1031PubMedCrossRefGoogle Scholar
  13. 13.
    Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G (2008) The anticancer immune response: indispensable for therapeutic success? J Clin Investig 118:1991–2001PubMedCrossRefGoogle Scholar
  14. 14.
    Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira J-P, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, André F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059PubMedCrossRefGoogle Scholar
  15. 15.
    Ciampricotti M, Hau C-S, Doornebal CW, Jonkers J, de Visser KE (2012) Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nat Med 18:344–346PubMedCrossRefGoogle Scholar
  16. 16.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–907PubMedCrossRefGoogle Scholar
  17. 17.
    Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman W-H, 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 71:1263–1271PubMedCrossRefGoogle Scholar
  18. 18.
    Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie J–J, Rochaix P, Girard J-P (2011) Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 71:5678–5687PubMedCrossRefGoogle Scholar
  19. 19.
    Dieu-Nosjean M-C, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman W-H, Cadranel J (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410–4417PubMedCrossRefGoogle Scholar
  20. 20.
    de Chaisemartin L, Goc J, Damotte D, Validire P, Magdeleinat P, Alifano M, Cremer I, Fridman W-H, Sautès-Fridman C, Dieu-Nosjean M-C (2011) Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res 71:6391–6399PubMedCrossRefGoogle Scholar
  21. 21.
    Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307PubMedCrossRefGoogle Scholar
  22. 22.
    Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh D (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813PubMedCrossRefGoogle Scholar
  23. 23.
    Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, Cheresh DA, Johnson RS (2008) Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456:814–818PubMedCrossRefGoogle Scholar
  24. 24.
    Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg S (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70:6171–6180PubMedCrossRefGoogle Scholar
  25. 25.
    Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, Katsaros D, O’Brien-Jenkins A, Gimotty P, Coukos G (2008) Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14:28–36PubMedCrossRefGoogle Scholar
  26. 26.
    Dirkx AEM, Oude Egbrink MGA, Kuijpers MJE, van der Niet ST, Heijnen VVT, Bouma-ter Steege JCA, Wagstaff J, Griffioen AW (2003) Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res 63:2322–2329PubMedGoogle Scholar
  27. 27.
    Quezada S, Peggs KS, Simpson TR, Shen Y, Littman DR, Allison JP (2008) Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 205:2125–2138PubMedCrossRefGoogle Scholar
  28. 28.
    Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Gröne H-J, Hämmerling GJ, Arnold B, Ganss R (2008) Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453:410–414PubMedCrossRefGoogle Scholar
  29. 29.
    Jiménez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N (2000) Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 6:41–48PubMedCrossRefGoogle Scholar
  30. 30.
    Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, Crosby E, Ryeom S, Felsher DW (2010) CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18:485–498PubMedCrossRefGoogle Scholar
  31. 31.
    Finlay D, Cantrell DA (2011) Metabolism, migration and memory in cytotoxic T cells. Nat Rev Immunol 11:109–117PubMedCrossRefGoogle Scholar
  32. 32.
    Onrust SV, Hartl PM, Rosen SD, Hanahan D (1996) Modulation of L-selectin ligand expression during an immune response accompanying tumorigenesis in transgenic mice. J Clin Investig 97:54–64PubMedCrossRefGoogle Scholar
  33. 33.
    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 (2008) Batf3 deficiency reveals a critical role for CD8alpha + dendritic cells in cytotoxic T cell immunity. Science (New York, N.Y.) 322:1097–1100Google Scholar
  34. 34.
    Schrama D, thor Straten P, Fischer WH, McLellan AD, Bröcker EB, Reisfeld RA, Becker JC (2001) Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14:111–121PubMedCrossRefGoogle Scholar
  35. 35.
    Yu P, Lee Y, Liu W, Chin RK, Wang J, Wang Y, Schietinger A, Philip M, Schreiber H, Fu Y-X (2004) Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 5:141–149PubMedCrossRefGoogle Scholar
  36. 36.
    Thompson ED, Enriquez HL, Fu Y-X, Engelhard VH (2010) Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J Exp Med 207:1791–1804PubMedCrossRefGoogle Scholar
  37. 37.
    Faget J, Biota C, Bachelot T, Gobert M, Treilleux I, Goutagny N, Durand I, Léon-Goddard S, Blay JY, Caux C, Ménétrier-Caux C (2011) Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells. Cancer Res 71:6143–6152PubMedCrossRefGoogle Scholar
  38. 38.
    Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M, Savino B, Colombo P, Jonjic N, Pecanic S, Lazzarato L, Fruttero R, Gasco A, Bronte V, Viola A (2011) Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208:1949–1962PubMedCrossRefGoogle Scholar
  39. 39.
    Hong M, Puaux A-L, Huang C, Loumagne L, Tow C, Mackay C, Kato M, Prévost-Blondel A, Avril M-F, Nardin A, Abastado J-P (2011) Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res 71:6997–7009PubMedCrossRefGoogle Scholar
  40. 40.
    Mrass P, Takano H, Ng LG, Daxini S, Lasaro MO, Iparraguirre A, Cavanagh LL, von Andrian UH, Ertl HCJ, Haydon PG, Weninger W (2006) Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J Exp Med 203:2749–2761PubMedCrossRefGoogle Scholar
  41. 41.
    Boissonnas A, Fetler L, Zeelenberg IS, Hugues S, Amigorena S (2007) In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med 204:345–356PubMedCrossRefGoogle Scholar
  42. 42.
    Calzascia T, Masson F, Di Berardino-Besson W, Contassot E, Wilmotte R, Aurrand-Lions M, Rüegg C, Dietrich P-Y, Walker PR (2005) Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity 22:175–184PubMedCrossRefGoogle Scholar
  43. 43.
    Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH (2003) Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424:88–93PubMedCrossRefGoogle Scholar
  44. 44.
    Mora JR, Cheng G, Picarella D, Briskin M, Buchanan N, von Andrian UH (2005) Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J Exp Med 201:303–316PubMedCrossRefGoogle Scholar
  45. 45.
    Mullins DW, Sheasley SL, Ream RM, Bullock TNJ, Fu Y-X, Engelhard VH (2003) Route of immunization with peptide-pulsed dendritic cells controls the distribution of memory and effector T cells in lymphoid tissues and determines the pattern of regional tumor control. J Exp Med 198:1023–1034PubMedCrossRefGoogle Scholar
  46. 46.
    Webster B, Ekland EH, Agle LM, Chyou S, Ruggieri R, Lu TT (2006) Regulation of lymph node vascular growth by dendritic cells. J Exp Med 203:1903–1913PubMedCrossRefGoogle Scholar
  47. 47.
    Nakanishi Y, Lu B, Gerard C, Iwasaki A (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462:510–513PubMedCrossRefGoogle Scholar
  48. 48.
    Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN (2006) Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440:890–895PubMedCrossRefGoogle Scholar
  49. 49.
    Kumamoto Y, Mattei LM, Sellers S, Payne GW, Iwasaki A (2011) CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input. Proc Nat Acad Sci USA 108:8749–8754PubMedCrossRefGoogle Scholar
  50. 50.
    Wong SBJ, Bos R, Sherman LA (2008) Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J Immunol (Baltimore, Md.: 1950) 180:3122–3131Google Scholar
  51. 51.
    Bos R, Sherman LA (2010) CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res 70:8368–8377PubMedCrossRefGoogle Scholar
  52. 52.
    Zou W, Restifo NP (2010) T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10:248–256PubMedCrossRefGoogle Scholar
  53. 53.
    Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, Shen F, Eaton SM, Gaffen SL, Swain SL, Locksley RM, Haynes L, Randall TD, Cooper AM (2007) IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 8:369–377PubMedCrossRefGoogle Scholar
  54. 54.
    Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31:787–798PubMedCrossRefGoogle Scholar
  55. 55.
    Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G, Liu R, Zou W (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149PubMedCrossRefGoogle Scholar
  56. 56.
    Clark RA, Huang SJ, Murphy GF, Mollet IG, Hijnen D, Muthukuru M, Schanbacher CF, Edwards V, Miller DM, Kim JE, Lambert J, Kupper TS (2008) Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med 205:2221–2234PubMedCrossRefGoogle Scholar
  57. 57.
    Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B (2011) CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Investig 121:2371–2382PubMedCrossRefGoogle Scholar
  58. 58.
    Cipponi A, Wieers G, van Baren N, Coulie PG (2011) Tumor-infiltrating lymphocytes: apparently good for melanoma patients. But why? Cancer Immunol Immunother 60:1153–1160PubMedCrossRefGoogle Scholar
  59. 59.
    Umansky V, Sevko A (2012) Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation. Cancer Immunol Immunother 61:275–282PubMedCrossRefGoogle Scholar
  60. 60.
    Germeau C, Ma W, Schiavetti F, Lurquin C, Henry E, Vigneron N, Brasseur F, Lethé B, De Plaen E, Velu T, Boon T, Coulie PG (2005) High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens. J Exp Med 201:241–248PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Laboratory of Immunobiology, Department of Molecular BiologyUniversité Libre de BruxellesGosseliesBelgium

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