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An optimized retinoic acid-inducible gene I agonist M8 induces immunogenic cell death markers in human cancer cells and dendritic cell activation.

Authors
  • Castiello, Luciano1, 2
  • Zevini, Alessandra3
  • Vulpis, Elisabetta4
  • Muscolini, Michela3
  • Ferrari, Matteo3
  • Palermo, Enrico3
  • Peruzzi, Giovanna5
  • Krapp, Christian6
  • Jakobsen, Martin6
  • Olagnier, David6
  • Zingoni, Alessandra4
  • Santoni, Angela3, 4
  • Hiscott, John7
  • 1 Istituto Pasteur Italia-Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161, Rome, Italy. [email protected] , (Italy)
  • 2 FaBioCell, Core Facilities, Istituto Superiore di Sanità, Rome, Italy. [email protected] , (Italy)
  • 3 Istituto Pasteur Italia-Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161, Rome, Italy. , (Italy)
  • 4 Department of Molecular Medicine, Sapienza University, Rome, Italy. , (Italy)
  • 5 Center for Life Nano [email protected], Istituto Italiano di Tecnologia, Rome, Italy. , (Italy)
  • 6 Department of Biomedicine, Aarhus University, Aarhus, Denmark. , (Denmark)
  • 7 Istituto Pasteur Italia-Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161, Rome, Italy. [email protected] , (Italy)
Type
Published Article
Journal
Cancer Immunology Immunotherapy
Publisher
Springer-Verlag
Publication Date
Sep 01, 2019
Volume
68
Issue
9
Pages
1479–1492
Identifiers
DOI: 10.1007/s00262-019-02380-2
PMID: 31463653
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

RIG-I is a cytosolic RNA sensor that recognizes short 5' triphosphate RNA, commonly generated during virus infection. Upon activation, RIG-I initiates antiviral immunity, and in some circumstances, induces cell death. Because of this dual capacity, RIG-I has emerged as a promising target for cancer immunotherapy. Previously, a sequence-optimized RIG-I agonist (termed M8) was generated and shown to stimulate a robust immune response capable of blocking viral infection and to function as an adjuvant in vaccination strategies. Here, we investigated the potential of M8 as an anti-cancer agent by analyzing its ability to induce cell death and activate the immune response. In multiple cancer cell lines, M8 treatment strongly activated caspase 3-dependent apoptosis, that relied on an intrinsic NOXA and PUMA-driven pathway that was dependent on IFN-I signaling. Additionally, cell death induced by M8 was characterized by the expression of markers of immunogenic cell death-related damage-associated molecular patterns (ICD-DAMP)-calreticulin, HMGB1 and ATP-and high levels of ICD-related cytokines CXCL10, IFNβ, CCL2 and CXCL1. Moreover, M8 increased the levels of HLA-ABC expression on the tumor cell surface, as well as up-regulation of genes involved in antigen processing and presentation. M8 induction of the RIG-I pathway in cancer cells favored dendritic cell phagocytosis and induction of co-stimulatory molecules CD80 and CD86, together with increased expression of IL12 and CXCL10. Altogether, these results highlight the potential of M8 in cancer immunotherapy, with the capacity to induce ICD-DAMP on tumor cells and activate immunostimulatory signals that synergize with current therapies.

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