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Sci Transl Med. 2018 Dec 5;10(470). pii: eaau5516. doi: 10.1126/scitranslmed.aau5516.

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

Author information

1
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
2
Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
3
CHU Sainte-Justine, Université de Montréal, Montreal, Quebec H3T 1C5, Canada.
4
Department of Computer Science and Operations Research, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
5
Department of Chemistry, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
6
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada. claude.perreault@umontreal.ca.

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.

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