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

doi:10.1016/j.celrep.2023.113047

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

Cell Rep. 2023 Sep 26;42(9):113047. doi: 10.1016/j.celrep.2023.113047. Epub 2023 Aug 30.

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
³ 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.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada. Electronic address: dbrooks@uhnresearch.ca.

Abstract

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

Keywords: CD4 T cell; CP: Immunology; CTLA4; T regulatory cell; cancer; dysfunction; exhaustion; immunotherapy; metabolism; transcriptomic signature; tumor immunology.

Publication types

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

MeSH terms

CD4-Positive T-Lymphocytes*
CD8-Positive T-Lymphocytes
Humans
Lymph Nodes
Neoplasms* / metabolism
T-Lymphocytes, Regulatory

Grants and funding

R01 AI085043/AI/NIAID NIH HHS/United States