Title

Regulation CD8 T cell dynamics and function in cancer

Abstract

T cells play a central role in immune responses against infections and oncogenesis. Unlike a typical acute immune response, which leads to pathogen clearance and memory T cell generation, anti-cancer immune responses are characterized by chronic antigen stimulation and T cell exhaustion. T cell exhaustion is a major obstacle in cancer immunity, and strategies to reinvigorate exhausted T cells represent a promising area in cancer immunotherapy. Recent studies suggest that exhausted T cells represent a heterogeneous and highly dynamic population originating from precursor CD8 T cells expressing the transcription factor TCF1 (encoded by the gene Tcf7) and displaying progenitor or stem-like properties. The molecular mechanisms regulating intratumor CD8 T cell dynamics, exhaustion, and function remain poorly understood. Our recent work identified a novel gene, Dapl1, that is specifically expressed in Tcf7+ progenitor CD8 T cells and involved in the regulation of intratumor CD8 T cell dynamics and exhaustion. Genetic ablation of Dapl1 renders tumor-infiltrating CD8 T cells functionally competent despite their expression of exhaustion markers. Consequently, Dapl1 ablation enhances antitumor immunity and synergizes with immune checkpoint inhibitors in tumor suppression. I will discuss the mechanism underlying the immunoregulatory role of Dapl1. In addition, I will talk about our recent work regarding the regulation of anticancer CD8 T cell responses by a metabolic signaling pathway downstream of co-stimulatory receptors.