Abstract
CD8 T cells mediate protective immune responses. However, persisting antigens such as chronic viruses or tumors redirect CD8 T cell differentiation to a suboptimal state called exhaustion. Exhausted T cells (TEX) lose their ability to persist long-term and initiate functional memory responses. Checkpoint blockade temporarily restores effector functions, but reinvigoration is not long-lasting. We recently demonstrated that microRNA-29a (miR-29a) attenuates exhaustion and promotes progenitor TEX. Therefore, we hypothesized that miR-29a epigenetically re-directs TEX differentiation and synergizes with checkpoint blockade. Indeed, we found that miR-29a epigenetically altered TEX and resulted in the differentiation of durable, persisting progenitor TEX with increased effector function upon aPD-1 blockade. Thus, combining ectopic expression of miR-29a with aPD-1 promoted T cell stemness while enhancing functional effector responses. Together, we suggest that miR-29a epigenetically reprograms TEX and promotes long-term persisting, functional CD8 T cell responses in response to checkpoint inhibitors.
We further investigated whether miR-29a modulated already differentiated TEX. Conditional overexpression of miR-29a at late stage of chronic infection promoted the expansion of progenitor-like T cells, and the phenotypic changes induced by miR-29a were stably maintained over time, suggesting that miR-29a has potential to rewire established TEX. To further explore the translational potential of miR-29a, an anti-PD-1-miR-29a conjugate was generated and shown to deliver miR-29a to PD-1+ T cell in vitro. Although the effects of the conjugate in vivo were modest, these findings provide a proof of concept that targeted miR-29a delivery may regulate TEX and represent a feasible approach for therapeutic development.
Collectively, this dissertation elucidates how miR-29a and aPD-1 blockade cooperatively reprogram CD8 T cell exhaustion, offering mechanistic insight and translational potential for enhancing sustained anti-viral and anti-tumor immune responses.