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.

An optimized retinoic acid-inducible gene I agonist M8 induces immunogenic cell death markers in human cancer cells and dendritic cell activation / Castiello, L.; Zevini, A.; Vulpis, E.; Muscolini, M.; Ferrari, M.; Palermo, E.; Peruzzi, G.; Krapp, C.; Jakobsen, M.; Olagnier, D.; Zingoni, A.; Santoni, A.; Hiscott, J.. - In: CANCER IMMUNOLOGY, IMMUNOTHERAPY. - ISSN 0340-7004. - (2019). [10.1007/s00262-019-02380-2]

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

Zevini A.;Vulpis E.;Muscolini M.;Zingoni A.;
2019

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.
2019
Cancer immunotherapy; Dendritic cells; Immunogenic cell death; Interferons; RIG-I
01 Pubblicazione su rivista::01a Articolo in rivista
An optimized retinoic acid-inducible gene I agonist M8 induces immunogenic cell death markers in human cancer cells and dendritic cell activation / Castiello, L.; Zevini, A.; Vulpis, E.; Muscolini, M.; Ferrari, M.; Palermo, E.; Peruzzi, G.; Krapp, C.; Jakobsen, M.; Olagnier, D.; Zingoni, A.; Santoni, A.; Hiscott, J.. - In: CANCER IMMUNOLOGY, IMMUNOTHERAPY. - ISSN 0340-7004. - (2019). [10.1007/s00262-019-02380-2]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1313555
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