MicroRNA-29a enhances and preserves stem-like CD8 T cell differentiation by regulating master epigenetic circuits of exhaustion
Year: 2026
Type: preprint
Abstract: CD8 T cells mediate protective immune responses. However, persisting antigens such as chronic viruses or tumors redirect CD8 T cell differentiation to a sub-optimal, epigenetically defined state called exhaustion. Exhausted T cells (T EX ) lose their ability to persist long-term and to initiate functional memory responses. Checkpoint inhibitor blockade temporarily restores effector functions, but immune reinvigoration is not long-lasting, due to the epigenetic stability of T EX . Therefore, epigenetic reprogramming of T EX leading to durable T cell responses is essential to improve disease control. Here, we demonstrate that a single microRNA (miR), miR-29a, epigenetically re-directs T EX differentiation and preserves T EX into a stem-like state, leading to long-term persisting progenitor T EX . MiR-29a rewires epigenetic maintenance programs, including downregulation of key exhaustion-associated regulators (Dnmt1, Dnmt3a, and Dnmt3b), alongside increased expression of progenitor- and stemness-associated genes such as Tcf7 and Il7r. These reprogrammed CD8 T cells are more sensitive to PD-L1 checkpoint blockade. Ectopic expression of miR-29a combined with aPD-L1 treatments enhances effector responses, while preserving T cell stemness. Together, our findings suggest that miR-29a can be leveraged to overcome current barriers to immune checkpoint blockade. Highlights MiR-29a rewires key exhaustion-associated epigenetic maintenance programs, while enhancing stemness-associated transcriptional circuits. MiR-29a drives extensive remodeling of accessible chromatin in T EX . MiR-29a preserves newly generated progenitor T EX in a durable, epigenetically defined stem-like state with increased effector function. MiR-29a synergizes with aPD-L1; while miR-29a preserves progenitor T EX state, addition of aPD-L1 enhances the cytotoxic potential of these progenitor T EX cells.
Authors: Xuebing Leng, Lance A. Buchness, Christine I. Rafie, Panagiotis I. Vlantis, Svetlana Ristin, Miguel A. Gallardo, Supipi L. Auwardt, Natasha K. Khatwani, Yuan-De Tan, Yuguang Ban, Corneliu M. Sologon, Benjamin B. Currall, Sion L. Williams, Kevin Van der Jeught, Jashodeep Datta, Alejandro Villarino, Aristeidis G. Telonis, Erietta Stelekati
Institutions: University of Miami, Sylvester Comprehensive Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Delivering miR-29a to enhance anti-viral and anti-tumor responses in vivo, A novel immunotherapy for pancreatic cancer using micro-RNA-29a, Epigenetic regulation of exhausted CD8 T cells via the miR-29a-TET2 axis, Disrupting MDSC-fibroblast interactions to overcome chemoimmunotherapy resistance in pancreatic cancer, The Sylvester Cancer Center Support Grant
OpenAlex ID: W7162799950