The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells

Amy E Baxter; Hua Huang; Josephine R Giles; Zeyu Chen; Jennifer E Wu; Sydney Drury; Katherine Dalton; Simone L Park; Leonel Torres; Brandon W Simone; Max Klapholz; Shin Foong Ngiow; Elizabeth Freilich; Sasikanth Manne; Victor Alcalde; Viktoriya Ekshyyan; Shelley L Berger; Junwei Shi; Martha S Jordan; E John Wherry

doi:10.1016/j.immuni.2023.05.008

The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8⁺ T cells

Immunity. 2023 Jun 13;56(6):1320-1340.e10. doi: 10.1016/j.immuni.2023.05.008.

Authors

Amy E Baxter¹, Hua Huang², Josephine R Giles³, Zeyu Chen¹, Jennifer E Wu³, Sydney Drury⁴, Katherine Dalton⁴, Simone L Park¹, Leonel Torres⁵, Brandon W Simone⁶, Max Klapholz⁷, Shin Foong Ngiow³, Elizabeth Freilich⁸, Sasikanth Manne¹, Victor Alcalde¹, Viktoriya Ekshyyan¹, Shelley L Berger⁹, Junwei Shi¹⁰, Martha S Jordan¹¹, E John Wherry¹²

Affiliations

¹ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
² Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
³ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁵ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁶ Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁷ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁸ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁹ Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁰ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: jushi@upenn.edu.
¹¹ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: jordanm@pennmedicine.upenn.edu.
¹² Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: wherry@pennmedicine.upenn.edu.

PMID: 37315535
DOI: 10.1016/j.immuni.2023.05.008

Abstract

CD8⁺ T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8⁺ T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1⁺ progenitor Tex cells to more differentiated TCF-1^- Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy.

Keywords: BAF; CRISPR-Cas9 screen; PBAF; SWI/SNF; T cell exhaustion; T cell memory; chromatin remodelling complexes; epigenetics; immunotherapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes*
Cell Differentiation
Chromatin
Chromatin Assembly and Disassembly*
Epigenesis, Genetic

Substances

Chromatin

Grants and funding

R21 AI144732/AI/NIAID NIH HHS/United States