Characterization of the HLA-F ligandome in T-cell lymphoma

Abstract

Abstract Identifying tumor-specific antigens across different types of malignancies and HLA haplotypes remains challenging. Recently, the expression of tumor-specific Human Endogenous Retroelements emerged as a potential new class of cytotoxic T-cell response mediators (1). HLA-F, a non-classic HLA-I molecule, has been hypothesized to present peptides to T-cells and to regulate immunity through interactions with distinct NK-cell receptors (2). HLA-F low genetic diversity and limited peptide repertoire represent an unexplored avenue in cancer immunotherapy. HLA-F-bound peptides were eluted from five patient-derived T-cell lymphoma cell lines and total T-cells purified from ten healthy donor PBMCs; Retroelement peptides were identified in the HLA-F ligandome. To quantify and validate their expression, RNA-sequencing data from the same samples were screened using ERVmap database (3). Lastly, to characterize their expression, we incorporate genome-wide characterization of DNA methylation patterns. We identified a set of retroelement peptides bound to HLA-F shared by patient-derived T-cell lymphoma cell lines but not total T-cells isolated from healthy donor PBMCs, suggesting a potential role of HLA-F in cancer-immune responses. Among those we characterized four tumor-specific retroelement peptides, validated by the presence of their RNA transcripts as well as by DNA integration and chromosomal location. Tumor-specific HLA-F-bound retroelement peptides hold great promise for the discovery of previously unknown tumor-specific markers and therapeutic targets. More importantly, the characterization of their immunogenicity may yield insights broadly applicable to a greater number of patients due to HLA-F monomorphism.