Myeloid Cell Reprogramming in the Glioblastoma Microenvironment: Extracellular Vesicles as a Novel Therapeutic Target to Rescue Immune Function - PROJECT SUMMARY/ABSTRACT This proposal details a career development and research plan over the course of 5 years in order to facilitate my development as an independent surgeon-scientist. As a neurosurgeon specializing in the treatment of brain tumors, I am acutely aware of the deficiencies in current treatments for glioblastoma (GBM), which has seen few advances in recent years. At Montefiore-Einstein, 50% of my effort is dedicated to basic and translational research, focused on the mechanisms of tumor-mediated immune suppression in GBM, a critical barrier to the development of effective novel therapies. This builds upon my prior research at Mayo Clinic, where I worked to understand the role of tumor-derived extracellular vesicles (EVs) in GBM-mediated immune suppression and target GBM-EVs as a novel therapeutic strategy. Previously, I found that PD-L1 expression in GBM-EVs was critical for the formation of a subset of immunomodulatory myeloid cells. Given the multimodal signaling capability of EVs, this work seeks to identify immune axes of myeloid cell polarization, as increasing evidence points to these cells as essential propagators of tumor-mediated immune suppression. Further, I will build upon my prior work in disrupting EV-target cell interactions as a therapeutic strategy, where I demonstrated that disruption of GBM-EV interactions with monocytes inhibited the induction of immunosuppressive myeloid cells and reduced T cell inhibition. Lastly, we will use a novel proteomics-based strategy to determine the critical pathways for EV release in GBM, opening a new avenue for therapeutic development. I will investigate the role of additional immune checkpoint axes in EV-mediated immune suppression. Preliminary data from my lab at Montefiore-Einstein demonstrates similar expression of immunomodulatory proteins in the tumor microenvironment and in EV-induced immunosuppressive monocytes. I will also investigate the therapeutic potential of several drugs to inhibit EV-myeloid cell interactions, both in vitro and with a novel in vivo model. This work is supported by a robust team of mentors lead by Dr. Xingxing Zang, one of the foremost authorities on novel immune checkpoint pathways. Dr. Chandan Guha, my co-mentor, has extensive experience in the study of extracellular vesicles, and will provide invaluable technical support and guidance. My Department Chair, Dr. Emad Eskandar, is a leading surgeon-scientist, and will provide significant mentorship and departmental support, including a generous startup package. I am also supported by collaborators with deep domain expertise in these areas. Drs. Jinan Behnan and Katayoun Ayasoufi are emerging leaders in the areas of patient-derived GBM propagation and tumor-mediated immune suppression, respectively, and Dr. Simone Sidoli, head of the Albert Einstein College of Medicine Proteomics core, has deep expertise in leading-edge proteomics, including EV proteomics. This career development proposal will allow me to complete the transition to being a fully independent surgeon-scientist, with the goal of successfully applying for R01 funding.
