Splicing inhibition enhances the antitumor immune response through increased tumor antigen presentation and altered MHC-I immunopeptidome
Abstract 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 cellsin vitroand decreases tumor growthin vivoin 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..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 12. Sept. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pierson, Alison [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| doi: |
10.1101/512681 |
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| PPN (Katalog-ID): |
XBI000424188 |
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| 245 | 1 | 0 | |a Splicing inhibition enhances the antitumor immune response through increased tumor antigen presentation and altered MHC-I immunopeptidome |
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| 520 | |a Abstract 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 cellsin vitroand decreases tumor growthin vivoin 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. | ||
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| 700 | 1 | |a Rouillon, Marine |4 aut | |
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| 700 | 1 | |a Renko, Zafiarisoa Dolor |4 aut | |
| 700 | 1 | |a Garcia, Camille |4 aut | |
| 700 | 1 | |a Ghosh, Michael |4 aut | |
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| 700 | 1 | |a Lobry, Camille |4 aut | |
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| 700 | 1 | |a Apcher, Sébastien |4 aut | |
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