T Cell Exhaustion

The tumor microenvironment (TME) profoundly shapes immune cell fate, often inducing CD8+ T cell and NK cell dysregulation that permits tumor progression. In extension to our previous work, this project aims to elucidate the epigenetic and transcriptional mechanisms governing CD8+ T cell exhaustion and NK cell suppression in tumors, with the ultimate goal of developing next-generation engineered cell therapies. Our team recently identified a critical immune receptor functioning as a key regulator of CD8+ T cell exhaustion at the epigenetic level. To dissect this pathway, we generated a novel CD8+ T cell-specific conditional knockout mouse model, enabling precise characterization of its intrinsic role in T cell exhaustion and reprogramming. In parallel, we are uncovering epigenetic checkpoints that limit NK cell cytotoxicity within tumors. Using CRISPR-based editing and functional profiling, we aim to identify novel epigenetic repressors that drive NK cell exhaustion and immune evasion. The translational component of this project integrates these insights into a dual-engineering CAR NK cell platform, in which lentiviral constructs co-express an NK cell-specific CAR and CRISPR/Cas9-mediated knockout of inhibitory epigenetic repressors. This strategy aims is expected to enhance NK cell cytotoxicity, persistence, and resistance to tumor cell-induced immune suppression.

Andrea Amalfitano, Monther Alalwan, Waled Warda.