Identification of a subset of tumor-reactive CD8 TIL expressing NKG2A in HNSCC and CRC
Midwinter Conference of Immunologists; Asilomar, CA
oregon; chiles; portland
Even though blocking the interaction of NKG2A with its ligand HLA-E is a promising strategy to restore the function of cytotoxic T cells and induce tumor cell killing, several aspects of the biology of NKG2A+ CD8 T cells remain to be understood to fully benefit from this therapeutic approach. Here, we characterize the expression of NKG2A on tumor-infiltrating CD8 T cells (CD8 TILs) in patients with head and neck squamous cell carcinoma (HNSCC) and microsatellite-stable colorectal cancer (CRC). Our results show that NKG2A is primarily expressed by a population of tumor-reactive CD8 TILs identified by coexpression of CD39 and CD103 (DP CD8). NKG2A expression was stable and maintained during in vitro expansion. Interestingly, while TCR stimulation in presence of IL-15 and TGF-B are thought to be responsible for NKG2A upregulation, our in vitro results suggest that other factors might be necessary to induce its expression on naive CD8 T cells. Ex vivo analysis of NKG2A+ DP CD8 TILs by scRNAseq and flow cytometry revealed that those cells were activated, more differentiated, and displayed a cytolytic profile suggesting a role in tumor recognition and killing. Finally, we found that, even though there was a high degree of clonal overlap between NKG2A+ and NKG2A- DP CD8, some CDR3 TCR sequences were enriched in one versus the other subset. Consequently, HPV-reactive cells were preferentially enriched in NKG2A- DP CD8 TILs. Altogether, our results provide evidence that NKG2A is expressed by tumor-reactive CD8 TILs in HNSCC and CRC. However, NKG2A-inducing factor(s) remain to be identified and might provide new potential drug targets to bolster anti-tumor immune responses in cancer patients.
Earle A. Chiles Research Institute
Fesneau, O; Samson, K; Rajamanickam, V; Ross, D; and Duhen, Thomas, "Identification of a subset of tumor-reactive CD8 TIL expressing NKG2A in HNSCC and CRC" (2022). Articles, Abstracts, and Reports. 5798.