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

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.

• Authors: Luciano Castiello, Alessandra Zevini, Elisabetta Vulpis, Michela Muscolini, Matteo Ferrari, Enrico Palermo, Giovanna Peruzzi, Christian Krapp, Martin Jakobsen, David Olagnier, Alessandra Zingoni, Angela Santoni, John Hiscott
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 68 Issue 9 Pg. 1479-1492 (Sep 2019) ISSN: 1432-0851 [Electronic] Germany
• PMID: 31463653 (Publication Type: Journal Article)

Chemical References

• Alarmins
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BBC3 protein, human
• Calreticulin
• HMGB1 Protein
• PMAIP1 protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Immunologic
• hydroxy-t-butylamidenelfinavir
• Interferons
• Caspase 3
• DDX58 protein, human
• DEAD Box Protein 58
• Nelfinavir

Topics

• Alarmins (immunology)
• Antigen Presentation (drug effects)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Calreticulin (metabolism)
• Caspase 3 (metabolism)
• Cell Differentiation
• Cell Line, Tumor
• DEAD Box Protein 58 (antagonists & inhibitors)
• Dendritic Cells (immunology)
• HMGB1 Protein (metabolism)
• Humans
• Immunization
• Interferons (metabolism)
• Melanoma (drug therapy)
• Molecular Targeted Therapy
• Nelfinavir (analogs & derivatives, pharmacology, therapeutic use)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Immunologic
• Signal Transduction