NKG2A expression on tumor reactive CD8 T cells is induced by IL-12

Abstract

Abstract Targeting the NKG2A/HLA-E pathway is a promising strategy to restore CD8 T cells functions, but several aspects of the biology of NKG2A+ CD8 T cells remain to be understood to fully benefit from it. Here, we characterized the NKG2A+ tumor infiltrating CD8 T cells (CD8 TILs) from patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). We showed that NKG2A was expressed by 10 to 15% of CD8 TILs, most of them resembling the previously described CD39+CD103+ (DP) CD8 TILs. scRNA-seq analysis revealed that NKG2A was upregulated as cells differentiated into DP CD8 TILs and acquired cytotoxic properties. NKG2A- and NKG2A+ DP CD8 TILs shared a significant TCR repertoire overlap, suggesting local upregulation of NKG2A. Using RNAscope we demonstrated that NKG2A+ DP CD8 TILs were enriched at the invasive margin and in the tumor bed where they might interact with HLA-E-expressing tumor cells. In contrast to previous results, we showed that CD4 T cells and APCs were required for NKG2A induction and this was dependent on CD40/CD40L interaction and IL-12 secretion. Altogether, our study provides evidence that NKG2A is expressed by tumor reactive CD8 TILs. It also highlights the dual role of IL-12, promoting cytotoxic T cell responses while inducing the expression of immune regulatory markers. The latter might negatively impact the anti-tumor immune response and should be taken into consideration in the future.