Deciphering the immunomodulatory functions of phosphatidylserine in the tumor microenvironment

PROJECT SUMMARY / ABSTRACT The tumor microenvironment (TME) is a complex assembly of cells, stromal tissue, and extracellular matrix that collectively create physical, biochemical, and immune barriers to cancer therapies. Phosphatidylserine (PS), a phospholipid typically confined to the inner leaflet of the plasma membrane, is believed to play a central role in the immunosuppressive characteristics of many TMEs. Aberrant exposure of PS on tumor cell membranes has been associated with negative prognoses and resistance to various treatments. This project seeks to understand this aberrant PS exposure with the ultimate goal of finding ways to overcome the challenges that currently limit its clinical exploitation. The central hypothesis of this proposal is that the exposure of PS on live (non-apoptotic) tumor cells contributes to immune suppression via its interaction with neighboring cells, including tumor associated macrophages. In Aim 1, the molecule(s) responsible for non-apoptotic PS exposure on tumor cells will be identified and their impact on tumor progression and immune responses in syngeneic mouse tumor models will be determined. Preliminary data implicate TMEM16F, a caspase-independent lipid scramblase, in non-apoptotic PS exposure on tumor cells. In Aim 2, the direct roles that PS plays in the immune-suppressive polarization of tumor-associated macrophages will be defined. Chimeric receptors for efferocytosis (CHEFs) will be used to either amplify or reprogram tumor-associated macrophage responses to PS recognition. Understanding the key molecular players and downstream immune responses to externalized PS could reveal new therapeutic strategies to target PS in tumors and thereby improve the immune system’s ability to attack solid tumors. During the course of this fellowship, the applicant will hone a comprehensive skill set encompassing technical expertise, sophisticated analytical skills, and effective communication, all of which will be essential for a career as an independent clinician investigator studying tumor immunology. Under the guidance of Dr. Kodi Ravichandran, a renowned expert in immunological responses across many disease states, and supported by a network of leading cancer biology and immunology experts, the applicant is well-positioned for achieving her career goals. The applicant’s institution, Washington University School of Medicine has a proven record of helping physician-scientists build successful careers. This proposed training plan is designed to facilitate the applicant’s transition into a pediatric oncologist and independent investigator dedicated to devising innovative therapeutic approaches for pediatric cancers.