Dissecting mechanisms of resistance underlying CD47-SIRPα inhibition in T-cell lymphomas

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Project Summary/Abstract: ! Over the recent years immunotherapeutic regimens have revolutionized the fate of solid malignancies and aggressive B-cell lymphomas but T-cell lymphoma (TCL) remains the orphan child. Identification and blockade of the CD47-SIRPa axis has created an opportunity for investigators to harness the innate immune cells. However early results from clinical trials have revealed that disruption of this signaling pathway is insufficient to clear tumor cells by macrophages. Thus, there is an unmet need to identify additional regulators of the macrophage checkpoint that confer resistance to CD47-mediated anti-tumor responses. I recently defined mechanisms by which CD47 antagonists induce anti-TCL response (Blood, 2019). However, marked heterogeneity across TCL models with poor correlation between CD47 expression and phagocytosis have led us to investigate molecular mechanisms that work with CD47 or independently from it in governing TCL recognition and eradication by macrophages. By combining modern next-generation immunophenotyping and single-cell sequencing; I will identify, mechanistically characterize, and therapeutically validate the compensatory signaling dependencies in CD47-resistant TCL models and primary samples. This will lay the foundation for future clinical trials of targeted immunotherapies in TCLs. I am an adult hematologist with substantial clinical and prior research experience in TCL who is seeking K08 support for mentored research in Dr. David Weinstock’s laboratory at Dana-Farber Cancer Institute (DFCI) with Dr. David Avigan, Beth Israel Deaconess Medical Center (BIDMC) acting as a co-mentor. My long-term career objective is to lead an independent research group focused on development of immunotherapy for patients with TCLs at an academic cancer center. The K08 award will provide the protected time I need for advanced training in CD47 biology and immunology, in particular, analysis of large-scale transcriptome and proteome datasets, experimental therapeutics and translational research. I will devote a minimum of 80% of my time to a focused research program on immune therapies for TCLs and will complement this with 20% of my effort dedicated to clinical care for adults with lymphomas. Dana-Faber Harvard Cancer Center (DF/HCC), comprised of DFCI and BIDMC is an internationally recognized research program with a number of expert researchers in the areas of cancer cell biology, immunology and computational biology. I have assembled an oustanding mentoring and advisory committee, consisting of Dr. Francis Luscinskas, Dr. Bruce Horwitz and Dr. Vassiliki Bousiottis, who will guide my research and training experiences. The expertise of my advisory committee will be complemented by a set of additional collaborators who are experts in their respective fields (Dr. Jim Lederer, Dr. Alex Shalek, and Kristen Stevenson). This research proposal is part of a structured plan with scientific, technical, clinical training and career development components with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on immunotherapy and clinical adult hematology.