UC Irvine

T cell exhaustion occurs when T cells are engaged by persistent antigen in the context of chronic infection and cancer. The formation of the exhaustion phenotype severely limits T cell effector function and survival, leading to diminished tumor and viral control. Immune checkpoints, which are upregulated in response to chronic T cell receptor engagement, promote the dysfunctional T phenotype. P-selectin glycoprotein ligand-1 (PSGL-1) is a known immune checkpoint protein, however the biological impact and therapeutic efficacy of targeting PSGL-1 in melanoma bearing mice is unknown. In this dissertation, we utilized in vivo melanoma models to investigate the impact on the anti-tumor T cell response after monoclonal antibody targeting of PSGL-1. We showed that anti-PSGL-1 treatment slowed the growth of PD-1-resistant melanoma tumors and promoted increased effector functions in tumor-infiltrating T cells. Further, we show that targeting PSGL-1 significantly reduced the immunosuppressive Treg frequencies in the tumor, leading to a more pro-inflammatory tumor microenvironment. While PSGL-1 is a known immune checkpoint, the role of CD38 in shaping the T cell response to acute and chronic viral infections is currently unknown. In this dissertation, we used an adoptive co-transfer approach of WT and Cd38-/- CD8+ T cells into WT mice that were subsequently infected with acute or chronic strains of lymphocytic choriomeningitis virus (LCMV) to investigate the impact of cell-intrinsic CD38 deletion on the T cell response to infection. We found that CD38 expression was important for the survival of virus-specific T cells over the course of infection. Further, while CD38 deletion did not prevent the formation of the exhaustion phenotype, we showed that T cells lacking CD38 had more proliferation and granzymeB production than WT cells, particularly the progenitor exhausted T cells (Tpex). Finally, we found that loss of CD38 caused reduced mitochondrial respiration in T cells, but only during chronic infection. Together, this dissertation provides new insight into the therapeutic efficacy of targeting PSGL-1, as well as uncovering a new role for CD38 in promoting survival of virus-specific T cells, while also limiting their effector function. This work details the impact that antibody targeting and genetic modulation of PSGL-1 and CD38 has on the exhaustion phenotype and is an important contribution to further our understanding of the proteins that shape the T cell response to infection and cancer.