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TCR-induced FOXP3 expression by CD8 + T cells impairs their anti-tumor activity.
- Source :
-
Cancer letters [Cancer Lett] 2022 Mar 01; Vol. 528, pp. 45-58. Date of Electronic Publication: 2021 Dec 29. - Publication Year :
- 2022
-
Abstract
- Adoptive cell transfer therapy using CD8 <superscript>+</superscript> T lymphocytes showed promising results eradicating metastatic malignancies. However, several regulatory mechanisms limit its efficacy. We studied the role of the expression of the transcription factor FOXP3 on CD8 <superscript>+</superscript> T cell function and anti-tumor immunity. Here we show that suboptimal T cell receptor stimulation of CD8 <superscript>+</superscript> T cells upregulates FOXP3 in vitro. Similarly, CD8 T cells transferred into tumor-bearing mice upregulate FOXP3 in vivo. Cell-intrinsic loss of FOXP3 by CD8 <superscript>+</superscript> T cells resulted in improved functionality after TCR stimulation and better antitumor responses in vivo. Inhibition of the FOXP3/NFAT interaction likewise improved CD8 <superscript>+</superscript> T cell functionality. Transcriptomic analysis of cells after TCR stimulation revealed an enrichment of genes implicated in the response to IFN-γ, IFN-α, inflammatory response, IL-6/JAK/STAT, G2M checkpoint and IL-2/STAT signaling in FOXP3-deficient CD8 <superscript>+</superscript> T cells with respect to FOXP3-wt CD8 <superscript>+</superscript> T cells. Our results suggest that transient expression of FOXP3 by CD8 <superscript>+</superscript> T cells in the tumor microenvironment restrains their anti-tumor activity, with clear implications for improving T cell responses during immunotherapy.<br /> (Copyright © 2021. Published by Elsevier B.V.)
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 528
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 34973390
- Full Text :
- https://doi.org/10.1016/j.canlet.2021.12.030