Abstract 4866: Attenuating CD8 T cell exhaustion and enhancing anti-tumor responses with microRNA-29a

Abstract CD8 T cells are important players of adaptive immunity, mediating protection against viral infections and cancer. CD8 T cell differentiation into memory T cells depends on effective clearance of the initial pathogen. Thus, chronically persisting pathogens or tumors result in a distinct T cell differentiation state, termed “exhaustion”. Exhausted T cells (TEX) are not able to generate optimal immune responses and provide immunological protection. Improving the function of exhausted T cells (TEX) by antagonizing surface inhibitory receptors, such as PD-1, is a potent immunotherapeutic strategy. However, a large number of patients do not benefit from immunotherapy or do not exhibit long-term protection, creating a need for improved immunotherapeutic strategies. Failure to respond to immunotherapy is attributed to the epigenetic stability of TEX and inability of immunotherapy to reverse TEX differentiation. Transcriptional and epigenetic analyses of TEX have identified cellular and molecular pathways associated with exhaustion. Most, if not all, of these exhaustion-associated pathways are regulated by microRNAs (miRs); therefore, miRs represent novel ideal targets for immunotherapy. We recently demonstrated that miR-29a redirects TEX differentiation into functional stem-like differentiation; therefore, presents an attractive target for novel immunotherapeutic strategies. Using ectopic overexpression of miR-29a as well as miR-29a deficient T cells, we demonstrate that miR-29a attenuates exhaustion and enhances the durability of protective T cell responses. Mechanistically, miR-29a directly targeted the 3’UTR of key transcriptional and epigenetic modulators, including Tet-2, Dusp2, Bach2, and Nfat. Importantly, miR-29a regulated CD8 T cell responses to TCR stimulation. Thus, miR-29a was found to regulate T cell differentiation by protecting CD8 T cells from deleterious overstimulation and, therefore, promoting functional anti-tumor responses. Thus, we propose that miR-29a is a novel regulator of TEX differentiation that can promote durable protective T cell responses and improve immunotherapy. Citation Format: Xuebing Leng, Lance Buchness, Christine Rafie, Natasha Khatwani, Miguel Gallardo, Svetlana Ristin, Luisa Cimmino, Aristeidis Telonis, Erietta Stelekati. Attenuating CD8 T cell exhaustion and enhancing anti-tumor responses with microRNA-29a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4866.