DOI: 10.1101/512681Jan 6, 2019Paper

Splicing inhibition enhances the antitumor immune response through increased tumor antigen presentation and altered MHC-I immunopeptidome

BioRxiv : the Preprint Server for Biology
Alison PiersonSebastien Apcher

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 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.

Related Concepts

Epitopes
Antigens
Histocompatibility Antigens Class I
Peptides
RNA Splicing
RNA, Messenger
Tumor Antigens
Inositol-1,4-bisphosphate 1-phosphatase
Inhibitors
Immunotherapy for Cancer

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