Abstract B021: In vivo gain-of-function screen identifies CREB5, a novel ECM modulator that promotes immunotherapy resistance via the Collagen-Lair1 axis

Abstract

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. Here, 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. Using transcriptional profiling, we showed CREB5 drives upregulation of extracellular matrix genes including collagen and collagen-stabilizing factors. We found CREB5 or collagen (Col1a1, Col4a1, or Col16a1) overexpressing tumors exhibit poor responses to anti-PD-1. 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 or collagen overexpression, suggesting that CREB5 overexpression drives resistance partly via collagen-LAIR1 inhibitory signaling. In summary, we have identified a gene that can induce fibroblast-like features in tumor cells to promote immunotherapy resistance. Further investigation of pathways that induces stromal mimicry in cancer cells could identify novel immunotherapy targets.

Citation Format: Payal Tiwari, Kayla Colvin, Sarah Kim, Ashwin Kammula, Seth Anderson, Or-Yam Revach, Maulik Vyas, Jessica A Talamas, Shadmehr Demehri, Kathleen Yates, John Doench, William C Hahn, Robert Manguso. In vivo gain-of-function screen identifies CREB5, a novel ECM modulator that promotes immunotherapy resistance via the Collagen-Lair1 axis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B021.