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\u2019s 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).<\/p>\n\n\n\n
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.<\/p>\n\n\n\n
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.<\/p>\n\n\n\n
University of Chicago | All Cancers | 2024<\/p>\n","protected":false},"excerpt":{"rendered":"
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\u2019s laboratory has been working for a number of […]<\/p>\n","protected":false},"featured_media":32157,"template":"","tax_cancer_type":[455],"tax_grant_type":[485],"tax_award_year":[741],"tax_institutions":[578],"tax_location_states":[559],"class_list":["post-32156","cri_scientists","type-cri_scientists","status-publish","has-post-thumbnail","hentry"],"acf":{"scientist_subhead":"CRI CLIP Investigator","quote":"CRI support is critical for carrying out this high-risk project investigating novel immune checkpoints as therapeuic targets.","scientist_last_name":"Gajewski","show_on_landing":true,"scientist_publish_until":"20280831"},"yoast_head":"\n