IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells

Olivier Fesneau, Kimberly A. Samson, Wesley Rosales, Bretton Jones, Tarsem Moudgil, Bernard A. Fox, Venkatesh Rajamanickam and Thomas Duhen ()
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Olivier Fesneau: Providence Cancer Institute
Kimberly A. Samson: Providence Cancer Institute
Wesley Rosales: Providence Cancer Institute
Bretton Jones: Providence Cancer Institute
Tarsem Moudgil: Providence Cancer Institute
Bernard A. Fox: Providence Cancer Institute
Venkatesh Rajamanickam: Providence Cancer Institute
Thomas Duhen: Providence Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A+ CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq on T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced on CD8 T cells differentiating into cytotoxic, CD39+CD103+ double positive (DP) cells, a phenotype associated with tumor-reactive T cells. This developmental trajectory leads to TCR repertoire overlap between the NKG2A– and NKG2A+ DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of NKG2A on CD8 T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8 T cells exposed to a TGF-β-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation.

Date: 2024
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DOI: 10.1038/s41467-024-54420-w

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