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  2. Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy

Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy

  • Nat Immunol. 2022 Dec 21. doi: 10.1038/s41590-022-01384-y.
Abbey A Saadey # 1 2 Amir Yousif # 1 3 Nicole Osborne 1 Roya Shahinfar 1 Yu-Lin Chen 1 Brooke Laster 1 Meera Rajeev 1 Parker Bauman 1 Amy Webb 4 Hazem E Ghoneim 5 6 7 8
Affiliations

Affiliations

  • 1 Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA.
  • 2 Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA.
  • 3 Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA.
  • 4 Biomedical Informatics Shared Resources, College of Medicine, The Ohio State University, Columbus, OH, USA.
  • 5 Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA. [email protected]
  • 6 Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA. [email protected]
  • 7 Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA. [email protected]
  • 8 The Pelotonia Institute for Immuno-Oncology, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. [email protected]
  • # Contributed equally.
Abstract

T cell dysfunctionality prevents the clearance of chronic infections and Cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits their response to immunotherapies, including immune checkpoint blockade (ICB). However, it is unclear which upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here we innovate an in vitro model system of stable human T cell dysfunction and show that chronic TGFβ1 signaling in posteffector CD8+ T cells accelerates their terminal dysfunction through stable epigenetic changes. Conversely, boosting bone morphogenetic protein (BMP) signaling while blocking TGFβ1 preserved effector and memory programs in chronically stimulated human CD8+ T cells, inducing superior responses to tumors and synergizing the ICB responses during chronic viral Infection. Thus, rebalancing TGFβ1/BMP signals provides an exciting new approach to unleash dysfunctional CD8+ T cells and enhance T cell immunotherapies.

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