Thomas F. Gajewski, MD, PhD, CRI CLIP Investigator University of Chicago Area of Research: All Cancers Checkpoint blockade therapy ((antibodies (Abs) targeting PD-1, CTLA-4, and LAG-3p)) has revolutionized cancer treatment. However, not all patients derive clinical benefit, and Dr. Gajewski’s laboratory has been working for a number of years aiming to understand mechanisms of resistance. Their work has uncovered multiple tumor and host-derived factors that impact on anti-tumor immunity and checkpoint blockade efficacy, including tumor cell-intrinsic oncogenic events, commensal microbiota differences, and germline variants in immune regulatory genes. Interestingly, during the course of this research, it has become clear that additional immune cell types besides T cells play major roles in immune regulation within the tumor microenvironment (TME). Yet, the major immune checkpoint Abs target almost exclusively T cells. As they have utilized RNA sequencing to characterize dysfunctional tumor antigen-specific CD8+ T cells within the TME in search for novel immune checkpoints, they made the critical observation that several of these molecules are expressed additionally by NK cells, gdT cells, and/or myeloid cells.This more promiscuous expression has been used as a prioritization criterion for generating knockout mouse models to understand this mechanism. The top candidates are KLRG1, GPR65, and GPNMB, and mice knocked out for each of these genes show a powerful improvement in immune-mediated tumor control in vivo, identifying them as critical negative regulators. In this proposal, Dr. Gajewski aims to understand the biology of these molecules further, to test their role in T cell adoptive transfer studies with a potential for rapid clinical translation, and to develop pharmacologic strategies to target them towards the goal of novel immunotherapeutics. Projects and Grants Novel immune checkpoints that regulate multiple immune cell types within the TME University of Chicago | All Cancers | 2024
