IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells 4593

Abstract Description While blockade of the NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response, several aspects of the biology of NKG2A+ CD8 T cells remain to be understood to fully benefit from this approach. We characterized the phenotype of NKG2A+ tumor infiltrating CD8 T cells (CD8 TIL) in patients with head and neck squamous cell carcinoma and mismatch repair-proficient colorectal cancer. NKG2A was expressed by 10 to 15% of CD8 TILs, with the dominant population co-expressing CD39+CD103 + (DP CD8), a phenotype of tumor-reactive cells. scRNA-seq analysis revealed that NKG2A was upregulated as cells differentiate into DP CD8 TILs and its expression was the highest on cells with high cytotoxic potential. This developmental trajectory led to TCR repertoire overlap between the NKG2A- and NKG2A+ DP CD8 TILs and shared antigen specificities. Using RNAscope, we found that NKG2A+ DP CD8 TILs were enriched in the tumor intraepithelial compartment where they might interact with HLA-E+ tumor cells. Mechanistically, CD4 T cells and APCs were required for NKG2A expression on CD8 T cells. More specifically, IL-12 was essential for its expression in a CD40/CD40L-dependent manner, in conjunction with TCR stimulation. Altogether, our study revealed that NKG2A, an inhibitory receptor, can be induced on human tumor-reactive CD8 T cells by IL-12, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)