Targeting antigen presentation to improve immunotherapy responses in breast cancer

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PROJECT SUMMARY/ABSTRACT: TARGETING ANTIGEN PRESENTATION TO IMPROVE IMMUNOTHERAPY RESPONSES IN BREAST CANCER Cancer immunotherapies, particularly those targeting the PD-1/L1 axis, are revolutionizing treatment paradigms. Although these therapies have proven effective in a wide variety of solid tumors, response rates to single agent anti-PD-1/L1 in breast cancer have been underwhelming, centering around 5%-15% of treated patients. However, given the durable responses observed in other tumor types, finding ways to increase breast cancer sensitivity to immunotherapy is a valuable endeavor. Our recent work in breast cancer and melanoma has identified an important role for major histocompatibility complex-II (MHC-II) expression on tumor cells as a mediator of enhanced anti-tumor immunity and subsequent response to immunotherapies targeting the PD- 1/PD-L1 axis. Furthermore, our preliminary studies suggest that both MHC-I and MHC-II expression (antigen- presenting molecules) on breast tumor cells directly influences the tumor microenvironment through expanded anti-tumor immunity. We found that activation of the Ras/MAPK pathway suppresses the expression of both MHC-I and MHC-II, and therefore may be an actionable target for enhancing antigen presentation to promote anti-tumor immunity and potentiate immunotherapy responses. Based on these data, we have initiated trials in both metastatic triple-negative breast cancer (TNBC) and ER+ breast cancer testing the efficacy of this combination. In this proposal, we will perform clinical validation of the molecular effects of MEK inhibition with anti-PD-L1 in ongoing clinical trials at our institution, as well as perform direct translational studies exploring the immune mechanism behind MEK inhibition that promotes anti-tumor immunity. Our central hypothesis is that therapeutic modulation of antigen presentation via MEK inhibition will promote immunotherapy response in breast cancer through enhanced MHC-I and MHC-II responses. The proposed studies will elucidate mechanism, validate clinical utility and identify new targets for combinations of therapies that promote anti-tumor immunity through enhancing antigen presentation. Thus, this proposal will use a translational approach to bring rational combinations of immunotherapy and molecularly targeted agents to breast cancer patients.