Abstract 2583: A T cell engager targeting cancer associated fibroblasts inhibits tumor growth and modulates the tumor microenvironment

Abstract Fibroblast activating protein (FAP) is an attractive target for therapeutic intervention being mainly expressed in malignant tissues. Previous studies have targeted FAP using a variety of methods yet failed in clinics. Here, we utilize FAP-targeted T cell engager (TcE) in KPCY tumor models to recapitulate a pre-clinical environment. The use of FAP- TcE efficiently depleted FAP+ fibroblasts in vitro and in vivo from tumors. This resulted in bystander killing of tumor cells and tumor growth control in vivo. This therapeutic effect was not dependent on priming via lymph node activation as shown in other publications. To understand the complex interactions with FAP expression, we perform comprehensive single cell RNA-sequencing profiling before and after FAP-TcE depletion to understand the pivotal genetic roles of FAP depletion in all cell types. This analysis initially revealed a T cell exhaustion phenotype with upregulated of PD-1 on T cells after FAP-TcE treatment. However, while addition of anti-PD-1 therapy significantly enhanced tumor efficacy, complete control was absent. RNA sequencing of the fibroblasts identified depletion of a myCAF-like fibroblast and an outgrowth of a mixed CAF population with phenotypes of both myCAF and iCAF. This population correlated with tumor growth, and cell cycle gene signatures. Future work will investigate the implications of this fibroblast population’s role in subverting immune suppression. Citation Format: Joshua R. Tagore, Robert Joseph Norgard, Pratha Budhani, Sai Charan Penikalapati, Jessica N. Egan, Di Feng, Leticia Corrales-Pecino, Anna Bachmayr-Heyda, Claudia Reichel-Voda, Abhishek Kashyap, Youli Xia, Sarah A. O’Brien. A T cell engager targeting cancer associated fibroblasts inhibits tumor growth and modulates the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2583.