Abstract A98: Young women's breast cancer demonstrates increased immune suppression through ciculating regulatory T cells and myeloid-derived supressor cells independent of stage or subtype.

Background: Women age 20-40 have a higher ten year risk for developing breast cancer than the five other leading cancers in this gender and age group combined. Women currently in their 30s have a 1/203 risk for breast cancer in the ensuing ten years. Cancers diagnosed in this age population of breast cancer have a higher risk for death for reasons that are not fully identified. Regulatory T cell (Tregs) and myeloid derived suppressor cells (MDSC) have a role in suppressing anti-tumor immunity. MDSC function through Jak/Stat pathway activation by generation of reactive oxygen species and/or arginase-1, and have been correlated pre-clinically with cancer progression and poorer prognostic features and outcomes. Our Young Women's Breast Cancer Translational Program seeks to identify immunologic differences potentially contributing to the poorer prognosis and potential targets for development of immunomodulatory treatment. Hypothesis: We hypothesized that newly diagnosed, treatment-naive young breast cancer cases would have higher percentage of circulating Tregs and MDSC with T cell suppressive function that similar age women without breast cancer. Methods: We conducted an IRB-approved, prospective translational study of women age 40 and under both affected and unaffected by breast cancer. Exclusion criteria included pregnancy, known autoimmunity or immunosuppressive medications, or other cancers. Tregs and MDSC were isolated from peripheral blood and phenotyped through standard protocols. The ability of MDSC to suppress T cell function were tested in co-culture assays for expression of activation marker CD25, production of gamma-interferon and production of arginase-1 and generation of reactive oxygen species. Results: As expected, Tregs were in higher number in young women with breast cancer than unaffecteds. Contrary to prior publications no difference was detected in number of MDSC identified in breast cancer (n=61) versus unaffected subjects (n=18). However, statistically significant increase in the MDSC ability to suppress T cell activation was identified in the breast cancer cohort with decreased CD25 expression and gamma-interferon production. MDSC from young women with breast cancer also secreted higher arginase-1 but not ROS from their MDSC. Level of MDSC suppression was independent of stage or biologic subtype of the breast cancer and did not correlate with the level of Tregs in the patient. Conclusions: The presence of equal rather than higher numbers of MDSC circulating in young onset breast cancer versus unaffected subjects was unexpected in comparison to prior publications. Our results may differ due to our larger sample size or the alignment by gender and age between the cohorts. Also, these are the first data on Tregs and MDSC to specifically focus on a young female population. Despite the equal numbers, MDSC from the breast cancer cohort demonstrated increased ability to suppress T cell function which was independent of cancer stage, biologic subtype or number of Tregs in the subject. These data suggest a functional difference to MDSC in the young breast cancer-bearing woman that could be exploited in even early stage breast cancer and that is not directly dependent on Tregs numbers. Moreover, the data indicate that unaffected young women have a higher than expected number of MDSC available for cancer to usurp and induce immune suppression. Identification of secretion of arginase-1 as a potential mechanism of immune suppression in young women's breast cancer warrants further investigation. Citation Format: Virginia F. Borges, Oscar Ramirez, Michelle Borakove, Elizabeth Manthey, Christina Finlayson, Anthony Elias, Martin McCarter, Kimberley Jordan, Jennifer Diamond, Nicole Kounalakis. Young women's breast cancer demonstrates increased immune suppression through ciculating regulatory T cells and myeloid-derived supressor cells independent of stage or subtype. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A98.