Investigating CREB5-driven mechanisms of immune therapy resistance

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Project Summary: Treatment with immune checkpoint inhibitors induce remarkable clinical responses in several cancer types. However, most cancer patients do not respond to immunotherapy, and patients who initially respond often exhibit acquired resistance. Understanding the universe of immune evasion strategies will enable the design of more effective immunotherapies. In preliminary studies, we identified genes that drive immune evasion by performing a genome scale in vivo CRISPR gain-of-function screen in tumors treated with anti-PD-1 antibodies; and discovered the transcription factor CREB5 as a top resistance mediator. We found CREB5 overexpressing tumors exhibit poor responses to anti-PD-1 and have fewer infiltrating CD8+ T cells. Using transcriptional profiling, we showed CREB5 drives upregulation of extracellular matrix genes including collagen and collagen- stabilizing factors. Collagen is the major ligand for the inhibitory receptor LAIR1, which is broadly expressed on T cells, B cells, NK cells, and myeloid cells. Deletion of LAIR1 in mice or overexpression of the decoy receptor LAIR2 in tumors abrogates the resistance-causing effect of CREB5 overexpression, suggesting that CREB5 overexpression drives resistance via collagen-LAIR1 inhibitory signaling. These observations form the foundation of our proposed studies to decipher the role of this tumor intrinsic mechanism of resistance to immune checkpoint therapy. Specifically, we propose to understand: 1) the molecular mechanisms governing CREB5 regulation and transcription; 2) CREB5-interacting proteins that drive collagen matrix deposition; and 3) the mechanism(s) by which LAIR1-collagen sensing inhibits anti-tumor immune responses. These studies will not only advance our understanding of immune regulation but will also provide new insights and targets useful for the development of new immunotherapy approaches for cancer.