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.
Original language | English |
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Pages (from-to) | 1479-1492 |
Number of pages | 14 |
Journal | Cancer Immunology and Immunotherapy |
Volume | 68 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sep 2019 |
Keywords
- Alarmins/immunology
- Antigen Presentation/drug effects
- Antineoplastic Agents/pharmacology
- 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
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Signal Transduction