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Differential regulation and function of tumor-infiltrating T cells in different stages of breast cancer patients

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Tumor Biology

Abstract

Breast cancer survival was associated with higher frequencies of CD8+ T cytotoxic T cells in infiltrating lymphocytes. On the other hand, the frequency of CD4+CD25+FoxP3+ regulatory T cells was inversely correlated with clinical outcomes of breast cancer. The regulation and interaction of different types of tumor-infiltrating T cells in different stages of breast cancer patients are still unclear. In this study, we examined the functions and regulations of CD8+ T cells and CD4+CD25+FoxP3+ T cells from resected tumors from 12 stage I, 24 stage II, and 20 stage III untreated breast cancer patients. We found that tumor-infiltrating CD8+ T cells from stage III patients were more refractory to T cell receptor (TCR) stimulation than those from stage I and stage II patients in terms of interferon gamma (IFN-γ) production and proliferation. On the other hand, tumor-infiltrating CD4+CD25+FoxP3+ T cells had higher proliferation in stage III tumors than in stage I and stage II tumors. In addition, we found that tumor-infiltrating CD4+CD25+ T cells can suppress CD8+ T cell inflammation ex vivo. Altogether, our data demonstrated that stage III tumors in breast cancer patients had a more immunosuppressive microenvironment.

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References

  1. Fan L, Strasser-Weippl K, Li J-J, St Louis J, Finkelstein DM, Yu K-D, et al. Breast cancer in China. Lancet Oncol. 2014;15:e279–89.

    Article  PubMed  Google Scholar 

  2. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol. 2009;36:237–49.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gloeckler Ries LA. Cancer survival and incidence from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist. 2003;8:541–52.

    Article  PubMed  Google Scholar 

  4. DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res. 2007;9:212.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gajewski TF, Schreiber H, Fu Y-X. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ascierto ML, De Giorgi V, Liu Q, Bedognetti D, Spivey TL, Murtas D, et al. An immunologic portrait of cancer. J Transl Med. 2011;9:146.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.

    Article  PubMed  Google Scholar 

  8. Mahmoud S, Lee A, Ellis I, Green A. CD8+ T lymphocytes infiltrating breast cancer: a promising new prognostic marker? Oncoimmunology. 2012;1:363–4.

    Article  Google Scholar 

  9. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  CAS  PubMed  Google Scholar 

  10. Galon J, Franck P, Marincola FM, Angell HK, Thurin M, Lugli A, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med. 2012;10:205.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bos R, Marquardt KL, Cheung J, Sherman LA. Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment. Oncoimmunology. 2012;1:1239–47.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bos R, Sherman LA. CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res. 2010;70:8368–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lindley S, Dayan CM, Bishop A, Roep BO, Peatman M, Tree TIM. Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes. 2005;54:92–9.

    Article  CAS  PubMed  Google Scholar 

  14. Horwitz DA. Regulatory T, cells in systemic lupus erythematosus: past, present and future. Arthritis Res Ther. 2008;10:227.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004;200:277–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 2011;11:119–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67.

    CAS  PubMed  Google Scholar 

  19. Boissonnas A, Scholer-Dahirel A, Simon-Blancal V, Pace L, Valet F, Kissenpfennig A, et al. Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity. 2010;32:266–78.

    Article  CAS  PubMed  Google Scholar 

  20. Watanabe MAE, Oda JMM, Amarante MK, Cesar Voltarelli J. Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev. 2010;29:569–79.

    Article  CAS  PubMed  Google Scholar 

  21. Knutson KL, Dang Y, Lu H, Lukas J, Almand B, Gad E, et al. IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. J Immunol. 2006;177:84–91.

    Article  CAS  PubMed  Google Scholar 

  22. Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev. 2010;21:3–10.

    Article  CAS  PubMed  Google Scholar 

  23. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfl V, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical utcome. Cancer Res. 2009;69:2000–9.

    Article  CAS  PubMed  Google Scholar 

  24. Mantovani A, Romero P, Palucka AK, Marincola FM. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet. 2008;371:771–83.

    Article  CAS  PubMed  Google Scholar 

  25. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28:4531–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–64.

    Article  CAS  PubMed  Google Scholar 

  28. Chen M-L, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A. 2005;102:419–24.

    Article  CAS  PubMed  Google Scholar 

  29. Nishikawa H, Jäger E, Ritter G, Old LJ, Gnjatic S. CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood. 2005;106:1008–11.

    Article  CAS  PubMed  Google Scholar 

  30. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–47.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Zhan at BGC Biotechnology Research Center for assisting in data analysis.

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Correspondence to Haidong Zou.

Additional information

Shiguang Zhu and Jun Lin contributed equally to this work.

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Zhu, S., Lin, J., Qiao, G. et al. Differential regulation and function of tumor-infiltrating T cells in different stages of breast cancer patients. Tumor Biol. 36, 7907–7913 (2015). https://doi.org/10.1007/s13277-015-3507-y

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  • DOI: https://doi.org/10.1007/s13277-015-3507-y

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