Factors contributing to T cell persistence in a tolerizing tumor environment

Abstract

Cancer is a leading cause of death worldwide, accounting for at least 10% of all deaths globally. Current therapies for cancer include surgical excision, chemotherapy and immunotherapy. CD8[+] T cells are adaptive immune cells responsible for eradicating tumor cells. However, these T cells can be rendered ineffective through tolerance. Yet in various mouse models and human patients, tolerant T cells persist. The aim of this project is to identify factors that support T cell persistence in a tolerizing tumor environment. Using a spontaneous prostate cancer model, we study antigen-specific T cells that have been shown to be locally tolerant in the prostate tumor environment. In this thesis, I compare the immune response in normal, antigen bearing, tumor transgenic and tumor-antigen transgenic mouse models. Results show that T cell infiltration and persistence in the tolerizing prostate environment is dependent on the presence of antigen and tumorigenic/tumor-related factors. Although antigen-specific T cells are locally tolerant in the prostate of tumor-antigen transgenic mice, they generally persist in the prostates of tumor transgenic mice regardless of whether antigen is present or not. Further analyses revealed that T cells infiltrate the prostate and can proliferate extensively in the tolerizing tumor environment due to the presence of antigen. Interestingly, antigen-specific T cells are depleted from the spleens of mice that express antigen in their prostates.

(cont.) This depletion from the spleen is correlated with low levels of IL-7R[alpha] expression and the presence of antigen in the prostate. Tumorigenic or tumor-related factors in the prostate also appear to be supporting CD8[+] T cell persistence. This thesis shows that persistence of antigen-specific T cells in the tumor environment is not dependent on IL-15 and IL-7; cytokines known to support proliferation and maintenance of persisting functional CD8[+] T cells. Some potential candidates are also discussed. More investigative work needs to be done to identify the role of these factors on T cell infiltration and persistence. In combination with tolerance-breaking strategies, persisting T cells may be excellent vehicles for delivering site-specific cancer immunotherapy.