Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure

Jean-Christophe Beltra; Mohamed S Abdel-Hakeem; Sasikanth Manne; Zhen Zhang; Hua Huang; Makoto Kurachi; Leon Su; Lora Picton; Shin Foong Ngiow; Yuki Muroyama; Valentina Casella; Yinghui J Huang; Josephine R Giles; Divij Mathew; Jonathan Belman; Max Klapholz; Hélène Decaluwe; Alexander C Huang; Shelley L Berger; K Christopher Garcia; E John Wherry

doi:10.1016/j.immuni.2023.11.005

Stat5 opposes the transcription factor Tox and rewires exhausted CD8⁺ T cells toward durable effector-like states during chronic antigen exposure

Immunity. 2023 Dec 12;56(12):2699-2718.e11. doi: 10.1016/j.immuni.2023.11.005.

Authors

Jean-Christophe Beltra¹, Mohamed S Abdel-Hakeem², Sasikanth Manne³, Zhen Zhang⁴, Hua Huang⁵, Makoto Kurachi⁶, Leon Su⁷, Lora Picton⁷, Shin Foong Ngiow³, Yuki Muroyama³, Valentina Casella⁸, Yinghui J Huang³, Josephine R Giles¹, Divij Mathew¹, Jonathan Belman³, Max Klapholz³, Hélène Decaluwe⁹, Alexander C Huang¹⁰, Shelley L Berger⁴, K Christopher Garcia¹¹, E John Wherry¹²

Affiliations

¹ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.
² Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt.
³ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁵ Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁶ Department of Molecular Genetics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan.
⁷ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Infection Biology Laboratory, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
⁹ Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Immunology and Rheumatology Division, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
¹⁰ Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, 1 Letterman Drive, Suite D3500, San Francisco, CA 94129, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹² Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. Electronic address: wherry@pennmedicine.upenn.edu.

PMID: 38091951
PMCID: PMC10752292 (available on 2024-12-12)
DOI: 10.1016/j.immuni.2023.11.005

Abstract

Rewiring exhausted CD8⁺ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Tex^prog) to intermediate (Tex^int) and terminal (Tex^term) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a and Tox. Stat5 directed Tex^int cell formation and re-instigated partial effector biology during this Tex^prog-to-Tex^int cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8⁺ T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rβ-pair fostered Tex^int cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.

Keywords: CD8(+) T cell; IL-2; PD-1 blockade; Stat5; Tex intermediate; Tox; epigenetic reprogramming; exhaustion; orthogonal IL-2:IL2Rβ.

MeSH terms

CD8-Positive T-Lymphocytes*
Gene Expression Regulation
Interleukin-2
Programmed Cell Death 1 Receptor / metabolism
Transcription Factors* / genetics

Substances

Transcription Factors
Interleukin-2
Programmed Cell Death 1 Receptor

Abstract

MeSH terms

Substances

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