Targeted activation of melanoma differentiation-associated protein 5 (MDA5) for immunotherapy of pancreatic carcinoma

Abstract

The RIG-I-like helicase melanoma differentiation-associated protein 5 (MDA5) is an innate immune receptor for double-stranded viral RNA (dsRNA) that, upon activation, induces a Type I interferon (IFN)-driven immune response. In the present study, we demonstrate that human und murine pancreatic cancer cells express functional MDA5 and are highly sensitive to MDA5-induced cell death. Activation of MDA5 by cytosolic delivery of the synthetic dsRNA analog poly(I:C) led to phosphorylation of the transcription factor IRF3, IFNβ production and upregulation of MHC-I expression. MDA5 signaling also induced tumor cell apoptosis via the intrinsic pathway and sensitized tumor cells toward extrinsic, Fas-mediated apoptosis. Systemic treatment of orthotopic pancreatic cancer-bearing mice with the MDA5 ligand resulted in activated CD8+ T cell tumor infiltration, an increased frequency of tumor antigen-specific CD8+ T cells and an immunogenic cytokine milieu in the tumor microenvironment. These effects were paralleled by MDA5-induced pronounced tumor cell death in situ and significantly prolonged survival in two different mouse models for pancreatic cancer, an immunotherapeutic response dependent on CD8+ T cells. Treated mice were further protected from subsequent tumor challenge. In summary, we identified MDA5 as a novel therapeutic target for overcoming apoptosis resistance and tumor-mediated immunosuppression in pancreatic cancer. MDA5 ligands link innate with adaptive immune mechanisms for effective tumor control.

Nucleic Acid Immunity

“…While normal healthy cells such as melanocytes and fibroblasts are quite resistant to RIG-I-induced apoptosis, tumor cells are highly susceptible to RIG-Iinduced cell death (Besch et al, 2009;Kubler et al, 2010). Based on this tumor selective activity and a favorable toxicity profile, RIG-I-specific ligands are currently being developed for immunotherapy of cancer (Duewell et al, , 2015Ellermeier et al, 2013;Schnurr & Duewell, 2013. Part of the potent antitumor activity of RIG-I ligands is its ability to promote crosspresentation of antigens to CD8 T cells and to induce cytotoxic activity (Hochheiser et al, 2016).…”

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

“…[5][6][7] Ligands targeting the RLR, RIG-I, and MDA-5 are also currently under development for cancer immunotherapy. 4,8,9 To transmit intracellular signaling, RLR and TLR employ different adaptor molecules; RLR utilize MAVS, 10 whereas TLR are coupled to MyD88 with the exception of TLR3, which exclusively signals via the adaptor TRIF. 11 Due to the different pathways triggered, cross-talk of receptor families can lead to enhanced immune responses.…”

Interferon regulatory factor�3 mediates Poly(I:C)-induced innate immune response and apoptosis in non‑small cell lung cancer

“…Treatment with BX795 or knockdown of IRF3 prior to Poly(I:C) transfection led to the inhibition of innate immunity. These findings suggested that the MDA5/ RIG-I/TBK1/IRF3 signalling pathway was initiated by intracellular Poly(I:C), and was intact in NSCLC cells, as in other cancer cells (14,27,28). Previous studies have revealed that Poly(I:C) induces apoptosis of prostate cancer cells, pancreatic cancer cells and other cells (27,28).…”

“…These findings suggested that the MDA5/ RIG-I/TBK1/IRF3 signalling pathway was initiated by intracellular Poly(I:C), and was intact in NSCLC cells, as in other cancer cells (14,27,28). Previous studies have revealed that Poly(I:C) induces apoptosis of prostate cancer cells, pancreatic cancer cells and other cells (27,28). Furthermore, the canonical apoptotic pathways, including the caspase-9-dependent intrinsic pathway and the caspase-8-dependent extrinsic pathway, engage Poly(I:C)-induced apoptosis to some degree (14,27).…”