Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens

Romain Darrigrand; Alison Pierson; Marine Rouillon; Dolor Renko; Mathilde Boulpicante; David Bouyssié; Emmanuelle Mouton-Barbosa; Julien Marcoux; Camille Garcia; Michael Ghosh; Mouad Alami; Sébastien Apcher

doi:10.1038/s42003-021-01801-2

Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens

Commun Biol. 2021 Mar 1;4(1):269. doi: 10.1038/s42003-021-01801-2.

Authors

Affiliations

¹ Université Paris-Saclay, Institut Gustave Roussy, Inserm, Immunologie des tumeurs et Immunothérapie, Villejuif, France.
² SATT Paris Saclay, Orsay, France.
³ Université Paris-Saclay, CNRS, BioCIS, Châtenay-Malabry, France.
⁴ Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
⁵ Institut Jacques Monod, CNRS U7592 Université Paris Diderot, Paris, France.
⁶ Institut Pasteur, Unité de Spectrométrie de Masse pour la Biologie (MSBio), Centre de Ressources et Recherches Technologiques (C2RT), USR 2000 CNRS, Paris, France.
⁷ Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
⁸ Université Paris-Saclay, Institut Gustave Roussy, Inserm, Immunologie des tumeurs et Immunothérapie, Villejuif, France. [email protected].

^# Contributed equally.

Abstract

The success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented on MHC-I molecules. We demonstrated that the splicing inhibitor isoginkgetin and its water-soluble and non-toxic derivative IP2 act at the production stage of the pioneer translation products (PTPs). We showed that IP2 increases PTP-derived antigen presentation in cancer cells in vitro and impairs tumor growth in vivo. IP2 action is long-lasting and dependent on the CD8⁺ T cell response against TAs. We observed that the antigen repertoire displayed on MHC-I molecules at the surface of MCA205 fibrosarcoma is modified upon treatment with IP2. In particular, IP2 enhances the presentation of an exon-derived epitope from the tumor suppressor nischarin. The combination of IP2 with a peptide vaccine targeting the nischarin-derived epitope showed a synergistic antitumor effect in vivo. These findings identify the spliceosome as a druggable target for the development of epitope-based immunotherapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity / drug effects*
Animals
Antigens, Neoplasm / metabolism*
Antineoplastic Agents, Phytogenic / pharmacology*
Biflavonoids / pharmacology*
Cancer Vaccines / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Fibrosarcoma / drug therapy*
Fibrosarcoma / immunology
Fibrosarcoma / metabolism
Fibrosarcoma / pathology
Histocompatibility Antigens Class I / immunology
Histocompatibility Antigens Class I / metabolism
Imidazoline Receptors / immunology
Imidazoline Receptors / metabolism
Lymphocyte Activation / drug effects
Lymphocytes, Tumor-Infiltrating / drug effects*
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Mice
Mice, Inbred C57BL
T-Lymphocytes / drug effects*
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Tumor Burden / drug effects
Tumor Microenvironment

Substances

Antigens, Neoplasm
Antineoplastic Agents, Phytogenic
Biflavonoids
Cancer Vaccines
Histocompatibility Antigens Class I
Imidazoline Receptors
Nisch protein, mouse
isoginkgetin derivative IP2