Abstract 2635: An epigenetic regulation targeting inhibitory receptors and attenuates CD8 T cell exhaustion in breast cancer

Abstract T cell exhaustion is a state of dysfunctional T cell response characterized by prolonged antigen exposure and diminished effector functions, a significant cause of tumor tolerance, and poor response to immune checkpoint blockade (ICB) therapy. T cell exhaustion is a highly dynamic process involved with a network of genetic and epigenetic regulation that program the T cell functions. Epigenetic regulation by microRNAs targets multiple genes involved in T cell function and is expected to be a major contributor to the functional programming of tumor-associated T cells. However, the underlying causal mechanisms remain to be determined. Here, we show that the microRNA miR-379-5p is a critical epigenetic regulator for promoting T cell function and suppressing exhaustion induced by chronic stimulation. The microRNA is identified by integrating bioinformatic interrogation of the miRNA databases cross-referencing with the TCGA database for genes involved in T cell functioning and their correlation with clinical outcomes, coupled with molecular profiling of miRNAs in experimental T exhaustion. Notably, the expression levels of miR-379-5p in tumor tissues, which encompass cancer cells and the surrounding stromal components, including immune cells, are closely associated with favorable prognosis of various cancer types. Further molecular and cellular characterization of miR-379-5p entailing cell culture, animal models, and patient-derived tumor organoids shows that it exerts suppressive effects by targeting specific sequences in the 3’ untranslated region (UTR) of critical immune checkpoint genes in T cells, thereby enhances the effector functions of cytotoxic T cells for tumor clearance. Ectopic expression of miR-379-5p shifts the evolution of primary T cells toward memory-like effector cells while silencing miR-379-5p induces exhaustion and abrogates the cytotoxic activity of primary T cells. We further demonstrate that transcriptional downregulation of miR-379-5p in T cells by a nuclear receptor transcription factor which is responsible for initiating the exhausting process impairs the tumor suppression function of T cells. Our studies indicate that miR-379-5p can function as a tumor suppressor by protecting T cells from exhaustion and bears the potential for developing novel strategies to improve the response to ICB therapy in breast cancer. Citation Format: You-Zhe Lin, Wan-Rong Wu, Feng-Chi Chung, Yi-Chun Shen, Chuan-Chun Lee, Hong-Wei Li, Guang-Jan Lin, Wei-Chung Chengx, Shao-Chun Wang. An epigenetic regulation targeting inhibitory receptors and attenuates CD8 T cell exhaustion in breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2635.