TCR signaling and cell cycle regulation in tumor-specific CD8 T cell dysfunction

PROJECT SUMMARY T cells have the potential to recognize and eliminate cancer cells. However, most often cancers progress in spite of the tumor-specific T cells present within tumors. While current immunotherapies such as immune checkpoint blockade can bring about long-lasting remissions in some patients with certain cancer types, most patients are not cured. Using a genetic liver cancer mouse model, we previously demonstrated that tumor-specific T cells, after entering malignant livers, rapidly differentiate to an early and then late dysfunctional state, encoded by distinct epigenetic programs. Late dysfunctional tumor-specific T cells failed to become functional again in response to immune checkpoint blockade, and we found that human tumor-infiltrating lymphocytes from patients with solid tumors shared key epigenetic hallmarks of late dysfunctional T cells from our mouse liver cancer model. Thus, a critical challenge for cancer immunotherapy is how to prevent or revert tumor-specific T cells from entering this epigenetically-enforced dysfunctional state. We now find that late TST fail to proliferate in response to T cell receptor stimulation, and we hypothesize that the barrier to functional rescue of late dysfunctional tumor-specific T cells is their inability to enter cell cycle in response to TCR stimulation. We will leverage our preclinical mouse cancer models and study TIL in liver and breast tumors from human patients to (i) understand how cell cycle kinetics and T cell receptor signaling defects change during dysfunctional differentiation, (ii) define how cell cycle and epigenetic changes determine functional rescue, and (iii) test strategies to overcome cell cycle and TCR signaling defects in late dysfunctional T cells. These studies will uncover critical insights into how cell cycle and T cell receptor signaling regulate the T cell epigenome and test therapeutically-applicable strategies to overcome barriers to tumor-specific T cell reprogramming, which may lead to improved cancer immunotherapies.