Cambios en la composicion del infiltrado inmunitario en tejido de cáncer de pulmónestado de inmunosupresion en la zona tumoral

  1. F. Perea 1
  2. M.M. Valenzuela-Membrives 2
  3. P. Bravo 2
  4. F. Garrido 1
  5. F. Ruiz-Cabello 1
  6. A. Sánchez-Palencia 2
  1. 1 Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves
  2. 2 Servicio de Cirugía Torácica, Hospital Universitario Virgen de las Nieves
Journal:
Revista española de patología torácica

ISSN: 1889-7347

Year of publication: 2020

Volume: 32

Issue: 4

Pages: 300-308

Type: Article

More publications in: Revista española de patología torácica

Abstract

Objective: Immune infiltration is a common characteristic of many solid human tumors. The immune system, both adaptive and innate, contributes to the immune surveillance of the tumor. We studied whether tumors avoid immune surveillance by inducing states of tolerance or through the inability of some immune subpopulations to penetrate the tumor nests. Methodology: Multiparametric flow cytometry analyses were used to study the composition and distribution of the different immune subpopulations in samples of peripheral blood, tumor tissue (TT), adjacent tumor tissue (ATT), distant non-tumor tissue (DNTT), tumor nests, the stroma and the invasive margin of the cancer in 61 patients with non-small cell lung cancer (NSCLC). Results: We detected a significantly higher percentage of B cells and a lower percentage of NK cells in TT than in DNTT. Memory T cells (CD4+ CD45RO+, CD8+ CD45RO+) and activated T cells (CD8+ DR+) were more prevalent in TT. Along with this immune activation, the percentage of T cells with immunosuppressive activity was greater in TT than in DNTT. B cells were practically non-existent in the tumor nests and were primarily located in the invasive margin. The dominant phenotype for NK cells in peripheral blood and DNTT was cytotoxic (CD56+ CD16+), while the presence of these cells significantly decreased in ATT and even more in TT. Finally, the immune response differed between adenocarcinoma and squamous cell histological types, according to the degree of tumor differentiation. These discoveries in the tumor infiltration of innate and adaptive immune cells contributes to a more complete immune response in NSCLC.

Bibliographic References

  • Molina JR, Yang P, Cassivi SD et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008; 83: 584–94.
  • Fridman WH, Pagès F, Sautès-Fridmanet al. Nature Rev Cancer. 2012; 12: 298–306.
  • Jemal A, Siegel R, Ward E et al. CA Cancer J. Clin. 2006; 56: 106–30.
  • Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews Immunology. 2006; 6: 295–307.
  • Atreya I, Neurath M.F. Immune cells in colorectal cancer: Prognostic relevance and therapeutic strategies. Expert Rev Anticancer. 2008; 8: 561–572.
  • Bindea G, Mlecnik B, Fridman WH et al. Natural immunity to cancer in humans. Curr Opin Immunol. 2010; 22: 215–222.
  • Galon J, Costes A, Sanchez-Cabo F et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313: 1.960–1.964.
  • Mlecnik B, Tosolini M, Kirilovsky A et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011; 29: 610–8.
  • Brambilla E, Le Teuff G, Marguet S et al. Prognostic effect of tumor lymphocytic infiltration in resectable non-small cell lung cancer. J of Clin Oncol. 2016; 34: 1.223–30.
  • Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010; 22: 231–7.
  • Pagès F, Kirilovsky A, Mlecnik B et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009; 27: 5.944–51.
  • Ronald J. deLeeuw, Sara E. Kost et al. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clinical Cancer Research. 2012; 18: 3.022–29.
  • Tao H, Mimura Y, Aoe K et al. Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer. 2012; 75: 95–101.
  • Duraiswamy J, Kaluza KM, Freeman GJ et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013; 73: 3.591–603.
  • Vivier E, Raulet DH, Moretta A et al. Innate or Adaptive Immunity? The Example of Natural Killer Cells Science. 2011; 331: 44–9.
  • Vivier E, Tomasello E, Baratin M et al. Functions of natural killer cells. Nature Immunology. 2008; 9: 503–1.
  • Sun JC, Lanier LL. Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity? Eur J Immunol. 2009; 39: 2.059–64.
  • Björkström NK, Riese P, Heuts F et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood. 2010; 116: 3.853–64.
  • Béziat V, Descours B, Parizot C et al. NK Cell Terminal Differentiation: Correlated Stepwise Decrease of NKG2A and Acquisition of KIRs. PLoS One. 2010; 5:e11966.
  • Jonsson AH, Yokoyama WM. Natural killer cell tolerance licensing and other mechanisms. Adv Immunol. 2009; 101: 27–79.
  • Kim S, Poursine-Laurent J, Truscott SM et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature. 2005; 436: 709–713.
  • Mamessier E, Sylvain A, Thibult ML et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. Journal of Clinical Investigation. 2011; 121: 3.609–22.
  • Goldstraw P. (Ed) Staging Manual in Thoracic Oncology. Editoral EXPress. 2015.
  • Galon J, Angell HK, Bedognetti D et al. The continuum of cancer immunosurveillance: Prognostic, predictive, and mechanistic signatures. Immunity. 2013; 39: 11–26.
  • Cai XY, Wang XF, Li J et al. Overexpression of CD39 and high tumoral CD39(+)/CD8(+) ratio are associated with adverse prognosis in resectable gastric cancer. Int. J. Clin. Exp. Pathol. 2015: 8: 14.757–14764.
  • Sundström P, Stenstad H, Langenes V et al. Regulatory T cells from colon cancer patients inhibit effector T-cell migration through an adenosine-dependent mechanism. Cáncer Immunol. Res. 2016: 3: 183–193.
  • Meloni F, Morosini M, Solari N et al. Foxp3 expressing CD4+ CD25+ and CD8+ CD28− T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Hum Immunol. 2006; 67:1–12.
  • Mizumoto N, Kumamoto T, Robson SC et al. CD39 is the dominant Langerhans cell-associated ecto-NTPDase: Modulatory roles in inflammation and immune responsiveness. Nat Med. 2002; 8: 358–365.
  • Huntington ND, Vosshenrich CAJ, Di Santo JP. Developmental pathways that generate natural-killercell diversity in mice and humans. Nature Reviews Immunology. 2007; 7: 703–714.
  • Carrega P, Morandi B, Costa R et al. Natural killer cells infiltrating Human Nonsmall-Cell Lung Cancer are enriched in CD56brightCD16- cells and display an impaired capability to kill tumor cells. Cancer 2008: 112: 863–875.
  • Bruno A, Focaccetti C, Pagani A et al. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. Neoplaisa 2013: 15: 133–142.
  • Jin S, Deng Y, Hao JW et al. NK cell phenotipic modulation in lung cancer environment. PLoS ONE 2014: 9: e109976.
  • Perea F, Bernal M, Sánchez-Palencia A et al. The absence of HLA class I expression in non-small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration. Int. J. Cancer 2017: 140: 888–899.