Identification of novel HLA-A*11:01-restricted HPV16 E6/E7 epitopes and T-cell receptors for HPV-related cancer immunotherapy

BACKGROUND: E6 and E7 oncoproteins are considered ideal antigens of T cell therapy for human papillomavirus (HPV)-related cancers. However, little is known about the epitopes of E6 and E7 presented by HLA-A*11:01, one of the most prevalent HLA types globally, especially in Asia. METHODS: We combined in silico and experimental approaches to identify endogenously processed HLA-A*11:01-restricted epitopes of HPV16 E6 and E7. The identified epitopes were then used to screen available T cell receptors (TCRs) from healthy donors through in vitro stimulation of peripheral blood mononuclear cells (PBMCs). RESULTS: E6(93-101) (TTLEQQYNK, TTL) and E7(89-97) (IVCPICSQK, IVC), two novel HLA-A*11:01-restricted T cell epitopes of HPV16, were identified to be endogenously presented on tumor cells. TTL- and IVC-specific TCRs were isolated from 11 healthy donors through in vitro stimulation of PBMC. The key TTL and IVC residues involved in TCR-pMHC interactions were mapped, and the consensus sequence was “xxLEQxYNK” and “xVxPIxxxK.” The TTL- and IVC-specific TCRs with high functional avidity were used to generate TCR-engineered T cells, specifically recognizing and killing corresponding tumor cell lines in vitro and in vivo. In addition, TTL and IVC-specific TCR-T cells also recognized and killed HPV16(+) patient-derived organoids. CONCLUSIONS: The HLA-A*11:01-restricted HPV16 E6/E7 epitopes and TCRs identified in this study may provide a new strategy for HPV-related cancer immunotherapy in HLA-A*11:01(+) patients.