Analyzing the HLA class I ligandome of colorectal cancer (CRC) and patient-matched normal tissues, Kikuchi et al. identified a shared tumor-associated cryptic peptide, HF10, that was non-canonically translated from the long non-coding RNA PVT1, which is downstream of MYC. PVT1 gene expression was increased in CRC samples and contributed to tumor development. Variants of PVT1 encoding HF10 all shared a unique ORF. HF10 underwent conventional antigen processing, and in patient TIL and PBMC samples, CD8+ T cell subsets specifically recognized the HF10-HLA-A24:02 complex. In vitro, HF10-reactive CD8+ T cells were cytotoxic against HF10-expressing cells.
Contributed by Lauren Hitchings
ABSTRACT: CD8+ T cells recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathological conditions such as cancer. Advances in proteogenomic analysis of HLA ligandomes have demonstrated that cells present a subset of cryptic peptides derived from non-coding regions of the genome; however, the roles of cryptic HLA ligands in tumor immunity remain unknown. In the present study, we comprehensively and quantitatively investigated the HLA class I ligandome of a set of human colorectal cancer (CRC) and matched normal tissues, showing that cryptic translation products accounted for approximately 5% of the HLA class I ligandome. We also found that a peptide encoded by the long non-coding RNA (lncRNA), PVT1, was predominantly enriched in multiple CRC tissues. The PVT1 gene is located downstream of the MYC gene in the genome and is aberrantly overexpressed across a variety of cancers, reflecting its oncogenic property. The PVT1 peptide was recognized by patient CD8+ tumor-infiltrating lymphocytes, as well as peripheral blood mononuclear cells, suggesting the presence of patient immune surveillance. Our findings show that peptides can be translated from lncRNAs and presented by HLA class I and that cancer patient T cells are capable of sensing aberrations in noncoding regions of the genome.