Abstract
Abstract CD8 T cells initiate potent anti-tumor immune responses. However, tumor cells employ PD-1 ligand, (PD-L1) to obstruct CD8 T cell responses and drive exhausted T cells (TEX) differentiation. TEX are characterized by sub-optimal functionality and inability to efficiently eliminate tumor cells. Checkpoint inhibitor therapy such as anti-PD-1 can partially restore the effector functions of TEX, but the stable epigenetic programs of TEX lead to the loss of reinvigoration and tumor relapse, providing a challenge for the efficacy of checkpoint blockade therapy. We recently demonstrated that miR-29a acts as a key regulator of TEX differentiation, promotes memory-like differentiation and attenuates exhaustion during chronic infection. Importantly, miR-29a favors the expansion of a progenitor TEX subset expressing the transcription factor TCF-1 that responds to immunotherapy. Therefore, we hypothesized that miR-29a can substantially alter TEX differentiation and synergize with checkpoint blockade to enhance anti-tumor immune responses. A well-established mouse model of chronic infection (LCMV clone-13) was used to induce TEX differentiation, with transcriptional and epigenetic profiles similar to TEX from human tumors. We found that combination of miR-29a overexpression and anti-PD-L1 treatment enhanced CD8 T cell expansion > 20 fold, whereas anti-PD-L1 alone marginally increased the number of CD8 T cells, suggesting that miR-29a synergizes with anti-PD-L1 to enhance CD8 T cell responses. Immune reinvigoration induced by anti-PD-L1 therapy is characterized by a partial reduction of inhibitory receptors and increase in effector responses. Instead, miR-29a overexpression combined with anti-PD-L1 promoted memory-like differentiation and long-term persistence of CD8 T cells, without compromising effector functions. Mechanistically, miR-29a synergized with anti-PD-L1 by inducing expression of a key memory-associated transcription factor, TCF-1, and antagonizing the master epigenetic regulator of exhaustion, TOX. To further understand whether miR-29a promotes only expansion of a progenitor TCF1+ subset or fundamentally alters TEX subset differentiation, equal numbers of miR-29a overexpressing and control TCF1+ CD8 T cells were isolated and adoptively transferred to secondary host mice followed by PD-L1 blockade. TCF1+ CD8 T cells with enforced miR-29a expression responded to PD-L1 blockade more efficiently than control TCF+ CD8 T cells. These results suggest that miR-29a fundamentally alters TEX differentiation by regulating key exhaustion-related transcriptional and epigenetic circuits. Therefore, we suggest that miR29a has the potential to be used as a novel therapeutic inducing robust and durable immune responses upon PD-1 therapy. Citation Format: Xuebing Leng, Svetlana Ristin, Christine Rafie, Lance Buchness, Alejandro Villarino, Erietta Stelekati. MicroRNA-29a synergizes with PD-1 therapy to regulate anti-tumor immunity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3807.
