CD8+ T cells are an important arm of the adaptive immune system with the capability to kill cells presenting non-self or mutated-self antigen through MHC I. In conditions of antigen persistence, such as cancer, CD8+ T cells differentiate into an “exhausted” state characterized by lack of cytotoxic capacity, diminished proliferative potential, and expression of co-inhibitory signaling molecules that further suppress T cell function. Antibodies that inhibit these co-inhibitory signaling pathways, such as PD-1 blocking antibodies, have been approved for the treatment of multiple cancer types. However, most cancer patients do not respond to existing immunotherapies, highlighting the need for add...

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CD8+ T cells are an important arm of the adaptive immune system with the capability to kill cells presenting non-self or mutated-self antigen through MHC I. In conditions of antigen persistence, such as cancer, CD8+ T cells differentiate into an “exhausted” state characterized by lack of cytotoxic capacity, diminished proliferative potential, and expression of co-inhibitory signaling molecules that further suppress T cell function. Antibodies that inhibit these co-inhibitory signaling pathways, such as PD-1 blocking antibodies, have been approved for the treatment of multiple cancer types. However, most cancer patients do not respond to existing immunotherapies, highlighting the need for additional strategies to improve adaptive immune responses against cancer. The goal of this Award will be to define the signaling inputs driving CD8+ T cell exhaustion and use this understanding to develop novel therapeutics for cancer. My first project will use cutting-edge techniques to define the CD8+ T cell infiltrate of breast cancer and identify therapeutic strategies for rejuvenating tumor-specific T cell function. Notably, this work will be the first to define the spatial organization of T cell clones in breast cancer tissue, using a technique I developed during my postdoctoral work to obtain T cell receptors from spatial transcriptomics data. My second project will use syngeneic mouse models of breast cancer to test novel therapeutic approaches to improve breast cancer-specific CD8+ T cell responses. The ultimate objective of this Award is to establish my laboratory at Baylor College of Medicine as a leader in the identification and development of therapeutic strategies for modulation of exhausted CD8+ T cell responses in cancer.

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