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Understanding Immunosuppressive Myeloid Cells and Immunotherapy Using Proteome Profiler™ Antibody Arrays
Monday, January 29, 2018 - 09:47
Prostate cancer (PCa) is the most common noncutaneous malignancy in men in the US. A significant fraction of advanced PCa treated with androgen deprivation therapy experience relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). The PCa tumor microenvironment is comprised of a complex mixture of epithelial and stroma cell types engaged in multifaceted heterotypic interactions functioning to maintain tumor growth and immune evasion. We recently uncovered the important role played by myeloid-derived suppressor cells (MDSCs) to mediate tumor immune evasion in aggressive PCa. Although, Immune checkpoint blockade (ICB) has elicited durable therapeutic responses across a number of cancer types, its impact of ICB on mCRPC has been disappointing. This signals the need to combine mechanistically-distinct ICB agents and/or override immunosuppression in the tumor microenvironment. We created a novel embryonic stem cell (ESC)-based chimeric mouse model of mCRPC engineered with signature mutations to study the response to single and combination immunotherapy. Consonant with early stage clinical trials experience, anti-CTLA4 or anti-PD1 monotherapy failed to impact disease progression. Similarly, modest anti-tumor activity was observed with combination ICB as well as monotherapy with targeted agents including Cabozantinib (tyrosine kinase inhibitor), BEZ235 (PI3K/mTOR inhibitor), and Dasatinib (tyrosine kinase inhibitor). In contrast, mCRPC primary and metastatic disease showed robust responses to dual ICB treatment together with either Cabozantinib or BEZ235, but not with Dasatinib which impaired T cell infiltration in the tumor. Taken together, we demonstrated that an antibody cocktail targeting CTLA4 and PD1 was insufficient to generate effective anti-tumor response, but combination of ICB with targeted therapy that inactivates PI3K signaling displayed superior synergistic efficacy through impairing MDSCs in the tumor microenvironment.
Understand the role of the myeloid-derived suppressor cells in the context of PCa immune evasion
Understand the therapeutic impact of dual ICB and kinase inhibitor therapy on mCRPC