Abstract 2959: Changes in the tumor stroma after MFP treatment in a MPA-induced murine mammary carcinoma model
Authors: Gonzalo Ricardo Sequeira, Ana Sahores, Tomas Dalotto-Moreno, Silvia Vanzulli, Laura Polo, Virginia Novaro, Caroline Lamb, Mariana Salatino, Claudia Lanari
Journal: Cancer Research (2017)

Abstract The role of the immune system in the regression of mammary carcinomas using endocrine therapies has been poorly investigated. The main goals of this study were: a) to evaluate differences in antiprogestin-induced regression of hormone receptor positive mammary carcinomas growing in immunocompetent or immunodeficient mice; b) to characterize the tumor infiltrating immune cells in mifepristone (MFP)-treated murine mammary carcinomas and c) to evaluate whether MFP treatment elicits immune protection in tumor re-challenge assays. Bone marrow (BM) cells from BALB/c-GFP mice were intravenously inoculated into NSG mice to establish the NSG/BM-GFP mouse model. GFP cells were detected in spleen, bone marrow, and blood from NSG/BM-GFP mice two months after BM-GFP cell inoculation. The murine mammary carcinoma 59-2-HI, originally induced by the administration of medroxyprogesterone acetate to BALB/c mice, regresses completely after MFP treatment. Tumors were orthotopically inoculated into NSG or NSG/BM-GFP female mice two months after BM grafting. When the tumors reached a size of approximately 50 mm2, low dose MFP pellets (0.2 mg) were administered in order to inhibit tumor growth. To characterize the infiltrating immune cells, tumors were excised after drug administration, disaggregated, and isolated cells were analyzed by FACs. For the re-challenge assay, tumors were excised 6 days after MFP treatment and animals were orthotopically re-inoculated with the same tumor in the opposite flank. Sham operated animals were used as controls. MFP inhibited the growth of tumors transplanted in either NSG or NSG/BM-GFP+ and no differences were observed between both groups, suggesting that the immune system is not a key factor mediating antiprogestin-induced tumor regression. Tissue remodeling was associated with an increase in lymphocytes (CD8+; T cells) and macrophages (CD11b+ F480+; p&amp;lt0.01 at day 3 and 6), and a decrease in the Treg subpopulation (CD4+ CD25+ Foxp3+; p&amp;lt0.05). These results led us to hypothesize that antiprogestin treatment could elicit a protective antitumor immune memory response by delaying tumor recurrence. To test this hypothesis we performed re-challenge assays using animals in which primary tumors have been previously excised. All tumors of control mice reached the ethical limit size (200 mm2) before day 47, while only half of the tumors in the MFP-treated group reached this size by this time (hazard ratio: 1.98). We conclude that antiprogestins induce tumor regression regardless of the presence of an impaired immune system and that the reduced intra-tumor Treg/CD8+ ratio observed in regressing tumors might be used as a predictive marker of treatment response. The re-challenge experiments agree with the hypothesis that regressing tumors expose intracellular antigens that generate a protective immune memory response, which in turn, could be associated with the long free relapse survival induced by endocrine therapy. Note: This abstract was not presented at the meeting. Citation Format: Gonzalo Ricardo Sequeira, Ana Sahores, Tomas Dalotto-Moreno, Silvia Vanzulli, Laura Polo, Virginia Novaro, Caroline Lamb, Mariana Salatino, Claudia Lanari. Changes in the tumor stroma after MFP treatment in a MPA-induced murine mammary carcinoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2959. doi:10.1158/1538-7445.AM2017-2959