Rebalancing TGFβ1/BMP Signaling Epigenetically Reprograms Fully Exhausted Human CD8 T Cells into a Functional State

Abstract

Abstract Epigenetic scarring of exhausted T cells (Tex) remains a major obstacle to achieving durable responses by T cell immunotherapies. While we established that de novo DNA methylation programs are causally linked to T cell’s full exhaustion and poor response to immune checkpoint blockade (ICB), major gaps remain in our current understanding of T cell exhaustion—(1) What are the upstream signals that regulate acquisition of exhaustion-specific epigenetic programs? (2) Can we remodel the epigenetic state of Tex to an ICB-responsive state? To address these questions, we developed a novel in vitro model of human T cell dysfunction. First, we demonstrated that chronic TCR stimulation of CD8 T cells is insufficient to develop T cell exhaustion. Instead, our integrative analyses of epigenetic and transcriptional changes in CD8 T cell subsets during chronic virus infections and cancer revealed TGFβ1 as the most significant upstream regulator linked to full exhaustion in mice and humans. Indeed, we found that post-effector TGFβ1 signaling accelerates full exhaustion in chronically stimulated CD8 T cells through stable epigenetic changes linked to impaired effector function and memory potential. Therapeutic rebalancing of TGFβ1/BMP signals by blocking TGFβ1 while boosting BMP signals not only restored effector function, but also unlocked memory programs in human Tex cells. This new therapeutic approach induced a superior anti-tumor activity of human T cells and synergized the ICB response in a murine model of chronic LCMV infection. Our findings highlight the role of TGFβ1/BMP signals in T cell exhaustion and propose a novel therapeutic strategy to epigenetically reprogram fully exhausted T cells, ultimately enhancing T cell immunotherapies.