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; Thomas Duhen

doi:10.1038/s41467-024-54420-w

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

Nat Commun. 2024 Nov 18;15(1):9988. doi: 10.1038/s41467-024-54420-w.

Authors

Olivier Fesneau¹, Kimberly A Samson¹, Wesley Rosales¹, Bretton Jones¹, Tarsem Moudgil¹, Bernard A Fox¹, Venkatesh Rajamanickam¹, Thomas Duhen²

Affiliations

¹ Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA.
² Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. [email protected].

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.

MeSH terms

Antigens, CD / genetics
Antigens, CD / metabolism
Apyrase
CD8-Positive T-Lymphocytes* / immunology
CD8-Positive T-Lymphocytes* / metabolism
Cell Differentiation / immunology
Colorectal Neoplasms / genetics
Colorectal Neoplasms / immunology
Colorectal Neoplasms / metabolism
HLA-E Antigens
Head and Neck Neoplasms / genetics
Head and Neck Neoplasms / immunology
Head and Neck Neoplasms / metabolism
Humans
Integrin alpha Chains / genetics
Integrin alpha Chains / metabolism
Interleukin-12* / immunology
Interleukin-12* / metabolism
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
NK Cell Lectin-Like Receptor Subfamily C* / genetics
NK Cell Lectin-Like Receptor Subfamily C* / metabolism
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism
Squamous Cell Carcinoma of Head and Neck / genetics
Squamous Cell Carcinoma of Head and Neck / immunology
Squamous Cell Carcinoma of Head and Neck / metabolism

Substances

NK Cell Lectin-Like Receptor Subfamily C
KLRC1 protein, human
Interleukin-12
Antigens, CD
Integrin alpha Chains
ENTPD1 protein, human
Receptors, Antigen, T-Cell
HLA-E Antigens
Apyrase