Laumont and Vincent et al. developed a proteogenomic approach to identify tumor specific antigens (TSAs) as MHC-bound peptides derived not only from mutated coding regions but also from aberrantly expressed noncoding regions of the genome (aeTSAs). In 2 murine cancer cell lines (CT26 and EL4) and 7 primary human tumors (4 B-ALL, 3 lung), the majority of MHC-presented TSAs originated from noncoding regions. In mice, the antitumor efficacy of vaccination with aeTSA-pulsed DCs largely depended on the level of aeTSA expression and the frequency of aeTSA-specific T cells – markers which could be evaluated in humans.
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.