Although tumor-specific CD8 T cells are found in human solid tumors, cancers progress, indicating that these T cells are dysfunctional. When naïve CD8 T cells encounter antigen in an inflammatory context (e.g. acute infection), a cell-intrinsic program is initiated that drives T cells to expand, produce effector cytokines, and differentiate into effector and memory T cells. In contrast, dysfunctional CD8 T cells in solid tumors express high levels of inhibitory receptors and fail to execute effector functions; however, the regulatory mechanisms underlying tumor-specific T cell dysfunction remain poorly defined. T cell-mediated immune responses are triggered by T cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC) on the surface of antigen presenting cells. The affinity of TCR:pMHC interaction is a critical determinant of CD8 T cell expansion and effector function in acute infections; while both low- and high-affinity antigens can activate naïve antigen-specific CD8 T cells, T cells with high-affinity TCR:pMHC interactions generally show superior effector function. However, little is known about how tumor antigen affinity impacts the activation of T cells, the induction of T cell dysfunction in progressing tumors, and T cell susceptibility to immunotherapeutic reprogramming. To investigate the role of TCR:pMHC affinity in T cell differentiation in progressing tumors, we generated tumor cell lines expressing altered peptide ligands (APL) derived from SV40 large T antigen epitope I (SV40-I). These APLs are recognized by SV40-I-specific transgenic CD8 T cells (TCRSV40-I) with varying functional avidity. We found that tumor-infiltrating TCRSV40-I encountering low- and high-affinity tumor antigens were equally activated and displayed similar expression levels of inhibitory receptors, such as PD1 and Lag3, suggesting that even very weak TCR ligations can induce a typical “exhaustion” phenotype. Strikingly, while high-affinity TCR:pMHC interactions led to complete loss of interferon gamma and tumor necrosis factor alpha production, T cells with low-affinity interactions remained functional and capable of producing high levels of these effector cytokines suggesting that contrary to our expectations, tumor-specific T cells with high-affinity TCR:pMHC interactions enter a profound state of dysfunction. Future experiments will test the impact of tumor antigen affinity on the efficacy of therapeutic reprogramming including checkpoint blockade, which will have important implications for immunotherapy.

Citation Format: Mojdeh Shakiba, Mary Philip, Andrea Schietinger. Impact of antigen affinity on T cell dysfunction in solid tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A093.