Utilizing self-specific CD8 T cells for the treatment of cancer

Abstract

Abstract CD8 T cells are potent effectors that monitor the body for infections as well as malignancies. CD8 T cell infiltration into tumors is correlated with better prognoses in many cancers. However, the tumor microenvironment is often toleragenic, which treatments like checkpoint inhibitors seek to overcome. Such treatments have been met with some success, but their benefits remain elusive for a subset of patients. Using a strict model of tolerance to intestinal self-antigen, we show that newly activated CD8 T cells respond best to checkpoint blockade therapy, while CD8 T cells in a toleragenic environment, even for a short time, do not respond. We have developed a therapeutic vaccination strategy that generates a targeted CD8 T cell response with renewed susceptibility to checkpoint blockade. Using heterologous prime boost vaccination model, we have refined tolerance reversal to a subset of self-antigen specific CD8 T cells, and eliminated the need for broadly immunostimulatory treatments. This model has been used to reverse tolerance in CD8 T cells specific for engineered antigens in the small intestine as well as naturally occurring self-antigens in the skin. The expanded populations of skin-specific CD8 T cells can be utilized for the treatment of melanoma. These melanocyte-specific CD8 T cells are functional and generate tissue resident memory (Trm) populations throughout the body, including the skin. Additionally, melanocyte-specific CD8 T cells can cooperate with neo-antigen specific CD8 T cells to aid in tumor clearance. By investigating tolerance reversal in self-specific CD8 T cells we have uncovered ways to improve upon current anti-cancer treatments and developed potentially translatable anti-cancer vaccine strategies.