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PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells
- Source :
- JCI Insight, Vol 6, Iss 2 (2021)
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical investigation, 2021.
-
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.
- Subjects :
- Immunology
Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 6
- Issue :
- 2
- Database :
- Directory of Open Access Journals
- Journal :
- JCI Insight
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.8b7de59e26a544eda70bdfbd5f4d8749
- Document Type :
- article
- Full Text :
- https://doi.org/10.1172/jci.insight.142513