PT  - JOURNAL ARTICLE
AU  - Alison Pierson
AU  - Romain Darrigrand
AU  - Marine Rouillon
AU  - Mathilde Boulpicante
AU  - Zafiarisoa Dolor Renko
AU  - Camille Garcia
AU  - Michael Ghosh
AU  - Marie-Charlotte Laiguillon
AU  - Camille Lobry
AU  - Mouad Alami
AU  - Sébastien Apcher
TI  - Splicing inhibition enhances the antitumor immune response through increased tumor antigen presentation and altered MHC-I immunopeptidome
AID  - 10.1101/512681
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 512681
4099  - http://biorxiv.org/content/early/2019/01/06/512681.short
4100  - http://biorxiv.org/content/early/2019/01/06/512681.full
AB  - The success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented by tumor cells on MHC class I molecules. Alternative translation events emerged as a rich source of TAs and generate the so-called Pioneer Translation Products (PTPs), which are peptides generated from unspliced mRNA. We demonstrated in vitro and in vivo that the splicing inhibitor isoginkgetin and a derived water-soluble and less toxic molecule, IP2, act at the production stage of the PTPs. We showed that IP2 increases PTP-derived antigen presentation in cancer cells in vitro and decreases tumor growth in vivo in an immune-dependent manner. Furthermore, IP2 treatment induces a long-lasting antitumor response. Finally, we observed that the epitope repertoire displayed on MHC-I molecules is altered upon treatment with IP2 with the modulation of pre-existing peptides and the emergence of novel antigens derived from both coding and allegedly non-coding sequences.Significance IP2 is a new efficient “first in class” immunomodulator of the MHC I presentation pathway. IP2 reduces the growth of sarcoma MCA205 and melanoma B16F10 tumors bearing the PTP-derived SL8 epitope and significantly extends mice survival. IP2 treatment reshape the cancer cell MHC-I immunopeptidome. These findings add to the understanding of the role of the splicing machinery in antigen production and presentation and identify the spliceosome as a druggable target to enhance cancer immunosurveillance.