Abstract
Ovarian carcinoma is one of the most severe cancers in women, with a high relapse rate and limited secondary treatment options. To assist research in novel treatment technologies, including CD8+ T cell-base immunotherapy, we examined the effect of tumor-infiltrating regulatory T cells (Tregs) in inhibiting CD8+ T cell inflammation. We found that compared to their peripheral blood counterparts, tumor-infiltrating Tregs exhibited more potent inhibitory function, which was associated with higher interleukin 10 (IL-10) production in tumor-infiltrating Tregs. Blockade of T cell immunoglobulin mucin 3 (TIM3), a regulatory molecule overrepresented on tumor-infiltrating Tregs, had significantly reverted Treg-mediated suppression. Moreover, expression of TIM3 on tumor-infiltrating Tregs was directly correlated with tumor size. Together, our results demonstrated that ovarian tumor-infiltrating Treg cells were more immunosuppressive than their peripheral blood counterparts in a TIM3-dependent fashion.
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Lowe KA, Chia VM, Taylor A, O’Malley C, Kelsh M, Mohamed M, et al. An international assessment of ovarian cancer incidence and mortality. Gynecol Oncol. 2013;130:107–14.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics: 2011. CA Cancer J Clin. 2011;61:69–90.
Coleman MP, Quaresma M, Berrino F, Lutz JM, De Angelis R, Capocaccia R, et al. Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol. 2008;9:730–56.
Winter WE, Maxwell GL, Tian C, Carlson JW, Ozols RF, Rose PG, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25:3621–7.
Du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzin. Cancer. 2009;115:1234–44.
McGray AJR, Hallett R, Bernard D, Swift SL, Zhu Z, Teoderascu F, et al. Immunotherapy-induced CD8+ T cells instigate immune suppression in the tumor. Mol Ther. 2014;22:206–18.
Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.
Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Investig. 2007;117:1167–74.
Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.
Govindaraj C, Scalzo-Inguanti K, Madondo M, Hallo J, Flanagan K, Quinn M, et al. Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment. Clin Immunol. 2013;149:97–110.
Barnett JC, Bean SM, Whitaker RS, Kondoh E, Baba T, Fujii S, et al. Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype. Gynecol Oncol. 2010;116:556–62.
Anderson AC. Tim-3, a negative regulator of anti-tumor immunity. Curr Opin Immunol. 2012;213–16.
Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205:2763–79.
Das A, Ellis G, Pallant C, Lopes ARR, Khanna P, Peppa D, et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol. 2012;189:3925–35.
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2010;10:490–500.
Sakuishi K, Ngiow SF, Sullivan JM, Teng MWL, Kuchroo VK, Smyth MJ, et al. TIM3(+)FOXP3(+) regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology. 2013;2, e23849.
Song H, Zhou Y, Li G, Bai J. Regulatory T cells contribute to the recovery of acute lung injury by upregulating Tim-3. Inflammation. 2015;38:1267–72.
Moorman JP, Wang JM, Zhang Y, Ji XJ, Ma CJ, Wu XY, et al. Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection. J Immunol. 2012;189:755–66.
Gautron A-S, Dominguez-Villar M, de Marcken M, Hafler DA. Enhanced suppressor function of TIM-3(+) FoxP3(+) regulatory T cells. Eur J Immunol. 2014;1–9.
Shevach EM. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;636–45.
Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187–94.
Read S, Malmström V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.
Serra P, Amrani A, Yamanouchi J, Han B, Thiessen S, Utsugi T, et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4 + CD25+ T cells. Immunity. 2003;19:877–89.
Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4:1206–12.
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Meimei Bu and Yizhen Shen contributed equally to this work.
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Bu, M., Shen, Y., Seeger, W.L. et al. Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD8+ T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. Tumor Biol. 37, 3949–3956 (2016). https://doi.org/10.1007/s13277-015-4237-x
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DOI: https://doi.org/10.1007/s13277-015-4237-x