Event Abstract Back to Event PROGESTERONE LINKS TUMOR-ASSOCIATED IMMUNOSUPPRESSION AND METASTASIS IN TRIPLE-NEGATIVE BREAST CANCER Tomas D'Alotto-Moreno1*, Juan Pablo Cerliani1, Diego Croci1, Mariana Salatino1 and Gabriel A. Rabinovich1 1 CONICET, Argentina The immune system plays key roles in the recognition and elimination of most tumors. Progesterone (Pg) can shape the immune response favoring a tolerogenic rather than a pro-inflammatory adaptive response. As hormone replacement therapies, supplementation and hormone-based contraceptives have been associated with an increase of malignant breast neoplasia we investigated how progestins can regulate different key immune cell populations in the tumor microenvironment and their influence to tumor progression. To address this issue we used the highly metastatic, triple-negative 4T1 breast tumor. Balb/c mice treated with Pg or its synthetic analog, medroxyprogesterone acetate (MPA), showed an increased frequency of Foxp3+ regulatory T cells (Tregs) in draining lymph nodes (DLN) and an impaired antitumor response elicited by a decreased production of IFN-γ by CD4+ T cells. Tregs in DLN of progestin-treated animals showed increased expression of CD44 and CTLA-4. CD44+ Tregs exhibited a more suppressive capacity in vitro in contrast to their CD44- counterpart and produced significantly more TGFβ-1. Concordantly, progestin-treated tumor-bearing mice showed a higher frequency of CD44+-Tregs and PD1+TIM3+ ‘exhausted’ CD8 T cells in the tumor. Both Pg and MPA favored in vitro Treg stable differentiation and expansion which ultimately resulted in a more robust suppression activity. Progestin-induced Treg differentiation could not be inhibited by the nuclear progesterone receptor (nPR) antagonists, Zk230211 or Mifepristone. Interestingly, CD4 T cells did not express detectable levels of nPR by qPCR but did express membrane progesterone receptor alfa (mPRα), gamma (mPRγ) and progesterone receptor membrane component type 1 (PGRMC1). In the presence of progestins, in vitro differentiated Tregs displayed a dose dependant upregulation of RANKL expression, a protein involved in breast stem cell maintenance and malignant transformation of tumors. When co-cultured, ex vivo sorted- or in vitro differentiated Tregs, induce a RANKL dependent expansion of CD44+ tumor stem cell-like population that formed tumor spheres, exhibited an EMT molecular signature and had augmented invasiveness and a metastatic phenotype. Interestingly when animals were treated with progestins the number of lung metastases was notably increased although primary tumor volume was not altered. In addition, injection of these 4T1 co-cultured with progestin-induced Tregs (iTregs) decreased overall survival of mice compared with 4T1 co-cultured with control iTregs. Our findings highlight the relevance of progestins in modulating immunoregulatory checkpoints and harnessing immunosurveillance in the tumor microenvironment and suggest a mechanism that involves RANKL-RANK signaling through which Tregs could directly promote a metastatic and aggressive phenotype on tumor cells. Keywords: Progesterone, regulatory T cells (T-Regs), breast cancer, metastasis, immunosuppresion Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Tumor immunology Citation: D'Alotto-Moreno T, Cerliani J, Croci D, Salatino M and Rabinovich GA (2015). PROGESTERONE LINKS TUMOR-ASSOCIATED IMMUNOSUPPRESSION AND METASTASIS IN TRIPLE-NEGATIVE BREAST CANCER. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00051 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 May 2015; Published Online: 14 Sep 2015. * Correspondence: Mr. Tomas D'Alotto-Moreno, CONICET, Buenos Aires, Argentina, tomasdalotto@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Tomas D'Alotto-Moreno Juan Pablo Cerliani Diego Croci Mariana Salatino Gabriel A Rabinovich Google Tomas D'Alotto-Moreno Juan Pablo Cerliani Diego Croci Mariana Salatino Gabriel A Rabinovich Google Scholar Tomas D'Alotto-Moreno Juan Pablo Cerliani Diego Croci Mariana Salatino Gabriel A Rabinovich PubMed Tomas D'Alotto-Moreno Juan Pablo Cerliani Diego Croci Mariana Salatino Gabriel A Rabinovich Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.