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.

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TARGETING ANTIGEN PRESENTATION TO IMPROVE IMMUNOTHERAPY RESPONSES IN BREAST CANCER This is a translational proposal that seeks to extend our preclinical studies, which identified synergy between MEK inhibitors and anti-PD-L1 immunotherapy, to two (2) human metastatic breast cancer trials testing the same combination. Tumor correlates associated with MEK inhibition in animals and subsequent response to immunotherapy will be evaluated in paired patient tumor biopsies; furthermore, we will perform laboratory experiments to optimize therapy sequence and schedule and confirm the functionality of MHC-II expression (induced by MEK inhibition) in tumor cells as a mediator of immunologic response. Successful completion of this work will elucidate possible clinical biomarkers for response or resistance to immunotherapy in breast cancer, as well as novel mechanisms of tumor immune-evasion.

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National Cancer Institute (NCI)
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Vanderbilt University Medical Center
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