Abstract 3236: T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

Abstract

Although much clinical progress has been made in harnessing the immune system to recognize and target cancer, there is still a significant lack of an understanding of how tumors evade immune recognition and the mechanisms that drive tumor resistance to both T cell and checkpoint blockade immunotherapy. Our objective is to understand how tumor-mediated signaling through inhibitory receptors, including PD-1, combine to affect the process of T cell recognition of tumor antigen and signal activation in melanoma patients. The broader goal of the project is to understand the basis of resistance to PD-1 blockade and potentially identify new molecular targets to enable T cells to overcome dysfunction mediated by multiple inhibitory receptors (IR). Our biophysical measurements have shown that that the activities of TCR-proximal signaling components affect T cell antigen recognition and sensitivity at the earliest stages of T cell stimulation. We have shown that T cell antigen recognition is influenced by PD-1 and other inhibitory receptors via Shp-1/2 by targeting CD28 and Lckby directly suppressing TCR-pMHC-CD8 binding. Phospho-proteomics and flow cytometry-based analysis of melanoma patient-derived T cells from PD-1 blockade responders and non-responders identified additional mediators, signaling components and pathways associated with blockade resistance. CRISPR/Cas9 mediated genome editing was utilized to determine if resistance is mediated by the continued signaling of multiple IRs by perturbing IR signaling in mouse models of PD-1 blockade.Targeting these interactions and understanding the basis of resistance to PD-1 blockade would potentially allow identification of novel biomarkers of resistance or new molecular targets to enable T cells to overcome dysfunction during PD-1 checkpoint blockade.