Durable epigenetic reprogramming of exhausted CD8 T cells by microRNA-29a 

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B220
Abstract ID: 5922

Presenting Author:
Lance A Buchness , Graduate Research Student at Univ. of Miami Miller Sch. of Med., Sylvester Comp. Cancer Ctr., Univ. of Miami Hlth. Sys.

Abstract:

Chronic antigen stimulation causes T cell exhaustion. Exhausted CD8 T cells (T_EX) have unique transcriptional and epigenetic profiles. Immunotherapy, including αPD-1, partially reinvigorates T_EX, however, responses are not sustained due to the inability to alter the epigenetic T_EX profile. We recently demonstrated that a single microRNA, miR29a, attenuates exhaustion and promotes durable CD8 T cell responses during chronic stimulation. Importantly, miR29a promotes the differentiation of progenitor T_EX, the subset that responds to αPD-1 therapy. Here, we hypothesized that miR29a epigenetically alters T_EX, resulting in durable reinvigoration upon αPD-L1. We overexpressed miR29a in TCR transgenic CD8 T cells and transferred transduced cells into mice infected with Lymphocytic Choriomeningitis Virus clone-13, a chronic virus that induces T_EX. MiR29a altered chromatin accessibility of CD8 T cells, suggesting miR29a is a novel epigenetic regulator of T_EX. Chromatin accessibility was increased at stem-like regions and decreased at T_EX-like regions. Interestingly, combination of miR29a overexpression and αPD-L1 further reinforced the miR29a effects and increased promoter accessibility and RNA transcription. Mechanistically, miR29a regulated TCR signaling, thus, prevented overstimulation and attenuated exhaustion. We suggest that miR29a induces durable reinvigoration via epigenetic remodeling of T_EX, and thus, synergizes with checkpoint inhibitor blockade.