T cell antigen discovery via signaling and antigen-presenting bifunctional receptors.

Abstract

CD8+ T cells recognize and eliminate tumors in an antigen-specific manner. Despite progress in characterizing the antitumor T cell repertoire and function, identifying their target antigens remains a challenge. Here, we describe the use of chimeric receptors called Signaling and Antigen-presenting Bifunctional Receptors (SABRs) in a novel cell-based platform for T Cell Receptor (TCR) antigen discovery. SABRs present an extracellular peptide-MHC complex and induce intracellular signaling via a TCR-like signal upon binding with a cognate TCR. We devised a strategy for antigen discovery using SABR libraries to screen thousands of antigenic epitopes. We validated this platform by identifying the targets recognized by public TCRs of known specificities. Moreover, we extended this approach for personalized neoantigen discovery. The antigen discovery platform reported here will provide a scalable and versatile way to develop novel targets for immunotherapy.