Abstract A217: TCR affinity determines the fate of T-cells in tumors

T-cell-mediated immune responses are triggered by T-cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC). In acute infections, affinity of TCR:pMHC interaction is a critical determinant of T-cell expansion and effector function. However, little is known about how tumor (neo) antigen affinity impacts T-cell differentiation and dysfunction in tumors. To investigate the functional and molecular programs determined by affinity, we generated an in vivo tumor model expressing altered peptide ligands (APL) derived from a native tumor neoantigen recognized by antigen-specific CD8 T-cells with varying functional avidity. While affinity did not impact T-cell activation in tumor draining lymph nodes, it drove distinct functional and molecular pathways at the tumor site: key transcription factors and effector molecules were regulated by signal strength, preserving a cell-intrinsic functional program in T-cells with lower-affinity interactions, while certain hallmarks of T-cell dysfunction, including the expression of some inhibitory receptors, were affinity-independent. RNAseq and ATACseq analyses revealed distinct affinity-dependent transcriptional and epigenetic programs in low- vs. high-affinity T-cells that drive their functional differences. Together these results reveal that TCR:pMHC affinity plays a critical role in defining the epigenetic and transcriptional states and ultimately fate of tumor-specific T-cells. Citation Format: Mojdeh Shakiba. TCR affinity determines the fate of T-cells in tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A217.