Immunogenic cell death of human ovarian cancer cells induced by cytosolic poly(I:C) leads to myeloid cell maturation and activates NK cells

Abstract

Owing to high rates of tumor relapse, ovarian cancer remains a fatal disease for which new therapeutic approaches are urgently needed. Accumulating evidence indicates that immune stimulation may delay or even prevent disease recurrence in ovarian cancer. In order to elicit proinflammatory signals that induce or amplify antitumor immune reactivity, we mimicked viral infection in ascites-derived ovarian cancer cells. By transfection or electroporation we targeted the synthetic double-stranded RNA poly(I:C) intracellularly in order to activate melanoma differentiation-associated gene-5 (MDA-5), a sensor of viral RNA in the cytosol of somatic cells. Cancer cells reacted with enhanced expression of HLAclass I, release of CXCL10, IL-6, and type I IFN as well as tumor cell apoptosis. Monocytes and monocyte-derived DCs (MoDCs) engulfed MDA-5-activated cancer cells, and subsequently upregulated HLA-class I/II and costimulatory molecules, and secreted CXCL10 and IFN-a. Further, this proinflammatory milieu promoted cytolytic activity and IFN-c secretion of NK cells. Thus, our data suggest that the engagement of MDA-5 in a whole tumor cell vaccine is a promising approach for the immunotherapy of ovarian cancer.

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

“…RLH ligands have been shown to induce the release of type I IFN in cancer cells mediated by IRF-3/7 and NF-kB signaling. 19,[21][22][23] To confirm intact RLH signaling in pancreatic cancer cells, we transfected Panc02 cells with ppp-RNA or poly(I:C), which induced IFN-b mRNA expression as well as CXCL10 and IL-6 secretion in a dose-dependent manner ( Figure 1a and Supplementary Figures 1a and b). In addition, treatment of Panc02 tumor cells with RLH ligands resulted in cell death (Figure 1b and Supplementary Figure 1c).…”

“…Others reported that treatment of human ovarian cancer cells with RLH ligands resulted in phagocytosis of apoptotic tumor cells by monocyte-derived DCs and DC activation. 22,23 Together, these findings indicate that RLH-induced tumor cell death may promote adaptive immunity against tumors. However, mechanisms leading to DC activation and the impact on tumor antigen cross-presentation by DCs, which defines immunogenic cell death, have not been explored.…”

“…19,20 RLH ligands have been evaluated as therapeutic agents in preclinical tumor models for melanoma, ovarian cancer and pancreatic cancer. 19,[21][22][23][24] Therapeutic efficacy was enhanced by combining RNAi-mediated gene silencing with RIG-I activation in a single RNA molecule. 21,24 A ppp-siRNA targeting the anti-apoptotic protein Bcl-2 to promote tumor apoptosis showed therapeutic efficacy in experimental melanoma.…”

Mouse Embryonic Stem Cells Have Underdeveloped Antiviral Mechanisms That Can Be Exploited for the Development of mRNA-Mediated Gene Expression Strategy

“…We first determined potency of these short ssRNA in eliciting antiviral responses in a human ovarian epithelial carcinoma cell line (SKOV3 cells), which have been previously used as a model to study the immunogenicity of different types of RNA [38][39][40]. Using IFNb expression as a benchmark for antiviral responses, our data showed that only 3p-ssRNA with longer than 60 nt induced IFNb, whereas the removal of the 3p group completely abolished this effect, as demonstrated in the case of 3p-80nt-ssRNA (Fig.…”

Codelivery of zoledronic acid and double-stranded RNA from core-shell nanoparticles

“…[51][52][53][54][55] One of the side effects of poly (I:C) is induction of toxic cytokines, so its use in cancer is limited. [56][57][58] In our study, by encapsulating zoledronic acid and poly (I:C) in LCP, the effective doses of both poly (I:C) and zoledronic acid could be decreased, so this formulation may have less toxic effects.…”