Noncoding regions are the main source of targetable tumor-specific antigens

Abstract

Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but few have been identified thus far. We therefore developed a proteogenomic approach to enable the high-throughput discovery of TSAs coded by potentially all genomic regions. In two murine cancer cell lines and seven human primary tumors, we identified a total of 40 TSAs, about 90% of which derived from allegedly noncoding regions and would have been missed by standard exome-based approaches. Moreover, most of these TSAs derived from nonmutated yet aberrantly expressed transcripts (such as endogenous retroelements) that could be shared by multiple tumor types. Last, we demonstrated that, in mice, the strength of antitumor responses after TSA vaccination was influenced by two parameters that can be estimated in humans and could serve for TSA prioritization in clinical studies: TSA expression and the frequency of TSA-responsive T cells in the preimmune repertoire. In conclusion, the strategy reported herein could considerably facilitate the identification and prioritization of actionable human TSAs.

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors

“…It is becoming increasingly clear that aberrantly expressed tumor-rejection antigens (including peptides corresponding to genes of retroviral origin, which have been integrated into the genome at some stage during evolution) may be relevant for anticancer immune surveillance in mice as well as in humans. 49 Experimental evidence arises not only from mass spectrometry-based analysis of peptide presentation on MHC class I molecules, 43,49 but also from the results of therapeutic vaccination studies with peptides corresponding to aberrantly expressed antigens. 49,50 When considering human tumors, Miller et al have reported that polyomavirus-specific T cells may represent up to 21% of the T cell specificities within the tumor mass of Merkel cell carcinoma (MCC).…”

“…49 Experimental evidence arises not only from mass spectrometry-based analysis of peptide presentation on MHC class I molecules, 43,49 but also from the results of therapeutic vaccination studies with peptides corresponding to aberrantly expressed antigens. 49,50 When considering human tumors, Miller et al have reported that polyomavirus-specific T cells may represent up to 21% of the T cell specificities within the tumor mass of Merkel cell carcinoma (MCC). 51 Besides virally driven tumors (e.g., MCC and HPV-derived malignancies), 20 potentially immunogenic endogenous retroviruses have recently been reported in clear-cell renal cell carcinoma patients.…”

Integrated Proteogenomic Deep Sequencing and Analytics Accurately Identify Non-Canonical Peptides in Tumor Immunopeptidomes

“…Often, MS-based immunopeptidomic discoveries are limited to the standard, available protein sequence database, usually containing only annotated protein-coding sequences. Recently, several studies have included protein sequences derived from the translation of transcripts identified from RNA-Seq, or from ribosome profiling, into MS-based searches 9,[23][24][25][26][27][28] . Overall, these studies warrant further development in many key aspects: Importantly, elevated false discovery rates (FDRs) for the non-canonical space can occur when MS reference data are populated with protein sequences derived from all potential three-or six-frame translations of transcribed regions 29 .…”

Proteogenomic discovery of cancer antigens: Neoantigens and beyond

“…Surprisingly, the peptides derived from noncoding regions accounted for approximately 10% of the MHC class I ligands in human B cells. Moreover, the group recently reported that cancer cells also present those cryptic peptides by MHC class I, which induced host anti‐cancer CD8 + T‐cell responses in mouse models . Our group independently searched the HLA class I ligandome of human colon cancer cell lines and a variety of primary cancer tissues and found that approximately 1% of the HLA ligands arose from noncoding regions (unpublished data).…”

“…Moreover, the group recently reported that cancer cells also present those cryptic peptides by MHC class I, which induced host anti-cancer CD8 + T-cell responses in mouse models. 36 Our group independently searched the HLA class I ligandome of human colon cancer cell lines and a variety of primary cancer tissues and found that approximately 1% of the HLA ligands arose from noncoding regions (unpublished data). These findings support the hypothesis of translation from, if not all, allegedly noncoding RNAs.…”