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
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.
