학술논문
PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells
Document Type
article
Author
Camille-Charlotte Balança; Anna Salvioni; Clara-Maria Scarlata; Marie Michelas; Carlos Martinez-Gomez; Carlos Gomez-Roca; Victor Sarradin; Marie Tosolini; Carine Valle; Frédéric Pont; Gwénaël Ferron; Laurence Gladieff; Sébastien Vergez; Agnès Dupret-Bories; Eliane Mery; Philippe Rochaix; Jean-Jacques Fournié; Jean-Pierre Delord; Christel Devaud; Alejandra Martinez; Maha Ayyoub
Source
JCI Insight, Vol 6, Iss 2 (2021)
Subject
Language
English
ISSN
2379-3708
Abstract
Tumor antigen–specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.