| Autor: |
Mathilde Boulpicante, Camille Garcia, Marie-Charlotte Laiguillon, Marine Rouillon, Romain Darrigrand, Camille Lobry, Michael Ghosh, Zafiarisoa Dolor Renko, Alison Pierson, Sébastien Apcher, Mouad Alami |
| Rok vydání: |
2019 |
| Předmět: |
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| DOI: |
10.1101/512681 |
| Popis: |
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.SignificanceIP2 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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