Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control

Mengdi Guo; Diala Abd-Rabbo; Bruna C. Bertol; Madeleine Carew; Sabelo Lukhele; Laura M. Snell; Wenxi Xu; Giselle M. Boukhaled; Heidi Elsaesser; Marie Jo Halaby; Naoto Hirano; Tracy L. McGaha; David G. Brooks

Cell Reports (Sep 2023)

Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control

Mengdi Guo,
Diala Abd-Rabbo,
Bruna C. Bertol,
Madeleine Carew,
Sabelo Lukhele,
Laura M. Snell,
Wenxi Xu,
Giselle M. Boukhaled,
Heidi Elsaesser,
Marie Jo Halaby,
Naoto Hirano,
Tracy L. McGaha,
David G. Brooks

Affiliations

Mengdi Guo: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
Diala Abd-Rabbo: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Bruna C. Bertol: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Madeleine Carew: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Sabelo Lukhele: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Laura M. Snell: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Microbiology and Immunology and Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
Wenxi Xu: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Giselle M. Boukhaled: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Heidi Elsaesser: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Marie Jo Halaby: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Naoto Hirano: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
Tracy L. McGaha: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
David G. Brooks: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada; Corresponding author

Journal volume & issue: Vol. 42, no. 9
p. 113047

Abstract

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Summary: CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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