| dc.description.abstract | T cells recognize several types of antigens in tumors, including aberrantly expressed, non-mutated proteins (self/shared-antigens; SSA) and mutated proteins or oncogenic viral proteins (tumor-specific antigens; TSA). Immunotherapies such as immune checkpoint blockade (ICB) can activate T cell responses against TSA, leading to tumor control, but also against SSA, causing immune related adverse events (IrAE). To improve anti-TSA immunity while limiting anti-SSA autoreactivity, we need to understand how tumor-specific CD8 T cells (TST) and SSA-specific CD8 T (SST) cells differentiate in response to cognate antigens during tumorigenesis. Therefore, we developed a novel genetic cancer mouse model in which we can track TST and SST differentiation longitudinally as liver cancers develop. We found that both TST and SST lost effector function, but while TST persisted long term and had a dysfunctional/exhausted phenotype (including expression of PD1, CD39, and TOX), SST exited cell cycle prematurely and disappeared from liver lesions. Interestingly, SST persisted in spleens in a TCF1+ PD1- state. Memory-like SST were not only unable to produce effector cytokines, but surprisingly, these TCF1+ SST failed to proliferate in response to anti-PD1/anti-PDL1 immune checkpoint blockade (ICB). Our studies identify a novel dysfunctional T cell state occupied by self/tumor-reactive T cells: a TCF1+ PD1- state lacking in effector function, demonstrating that the type/specificity of tumor antigen may determine tumor-reactive T cell differentiation. | |
