Understanding Immunosuppressive Myeloid Cells and Immunotherapy using Proteome Profiler™ Arra

Speaker: Xin Lu, PhD John M, and Mary Jo Boler Assistant Professor, University of Notre Dame

Speaker Biography: Dr. Xin Lu develops novel insights into the genetic and molecular mechanisms of prostate tumor progression, tumor immunology and treatment resistance. He applies such knowledge to enhance the efficacy of therapeutic interventions for prostate cancer patients. Through his Ph.D. research at Princeton University and postdoctoral research at MD Anderson Cancer Center, Dr. Lu has made many contributions towards developing a mechanistic understanding and identifying therapeutic interventions for breast cancer and prostate cancer. He has published over 20 research and review articles, including the most recent publication in Nature, targeting immunosuppressive myeloid cells to enhance immunotherapy for advanced prostate cancer. His research team at University of Notre Dame and Indiana University Simon Cancer Center is actively investigating in-depth mechanisms of myeloid cell regulation and targeting in prostate cancer and other forms of malignancy including rare cancers. Dr. Lu sincerely welcomes opportunities of collaboration from both academic and industrial arenas. In this webinar presentation, Dr. Lu will discuss how he used antibody arrays to interrogate signaling changes associated with immunotherapy in animal models.

WEBINAR: Understanding Immunosuppressive Myeloid Cells and Immunotherapy using Proteome Profiler™ Arrays

Abstract: 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.

SPONSORED BY: Bio-Techne

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