Exploiting poly(I:C) to induce cancer cell apoptosis

Abstract

TLR3 belong to the Toll-like receptors family, it is mainly expressed on immune cells where it senses pathogen-associated molecular patterns and initiates innate immune response. TLR3 agonist poly(I:C) was developed to mimic pathogens infection and boost immune system activation to promote anti-cancer therapy. Accordingly, TLR agonists were included in the National Cancer Institute list of immunotherapeutic agents with the highest potential to cure cancer. Besides well known effects on immune cells, poly(I:C) was also shown, in experimental models, to directly induce apoptosis in cancer cells expressing TLR3.This review presents the current knowledge on the mechanism of poly(I:C)-induced apoptosis in cancer cells. Experimental evidences on positive or negative regulators of TLR3-mediated apoptosis induced by poly(I:C) are reported and strategies are proposed to successfully promote this event in cancer cells.Cancer cells apoptosis is an additional arm offered by poly(I:C), besides activation of immune system, for the treatment of various type of cancer. A further dissection of TLR3 signaling would contribute to greater resolution of the critical steps that impede full exploitation of the poly(I:C)-induced apoptosis. Experimental evidences about negative regulator of poly(I:C)-induced apoptotic program should be considered in combinations with TLR3 agonists in clinical trials.

TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer

“…Furthermore, we also observed for the first time that TLR3 expression on cancer cells is significantly associated with cleaved caspase-3 expression in a cohort of 45 human primary adenocarcinoma NSCLC. The association between TLR3 and caspase-3 expression, as a proof of the activation of apoptosis cascade in lung cancer, is supported by evidences in other cellular models of different cancer types, including breast, melanoma, head and neck, prostate, renal carcinoma, colon, and cervical cancers [10,11].…”

“…This unusual function of tumoral TLR3 has increased clinical interest in its targeting, prompting efforts to exploit the direct apoptotic effects of TLR3 on cancer cells [3]. Evidences on hepatocellular carcinoma (HCC), neuroblastomas or esophageal squamous cell carcinoma showed that TLR3 expression by the tumor parenchyma has been associated with a favorable prognosis (reviewed in [11,12]), and we recently observed that in early NSCLC, TLR3 expression on cancer cells is also significantly associated with good overall survival [13].…”

HDAC6, A Novel Cargo for Autophagic Clearance of Stress Granules, Mediates the Repression of the Type I Interferon Response During Coxsackievirus A16 Infection

“…These data suggested that CA16 repressed SG accumulation, which was closely related to autophagy. Poly I:C and CA16 could induce apoptosis (Zhu et al, 2013;Bianchi et al, 2017). To investigate whether poly I:C or CA16 induced apoptosis to promote the SGs-targeted autophagy, we applied Z-VAD-FMK, an apoptosis inhibitor, to repress apoptosis to investigate degradation of poly I:C-induced SGs which caused by CA16.…”

Development of Drugs Based on High-Polymeric Double-Stranded RNA for Antiviral and Antitumor Therapy

“…The ability of dsRNA to induce synthesis of IFN and other cytokines is a basis for diversity of their immunomodulatory properties. It has been shown that dsRNA causes an increase in absorption, metabolic and bactericidal activity of phagocytic cells (macrophages, neutrophils), activity of natural killers (NK), and maturation and activation of DC; this leads to activation of CD8+ and CD4+ T cells [44]. Thus, dsRNAs play a role of some functional linkers between innate and acquired immunity systems, providing a fast and productive defensive response to an infectious challenge.…”

“…Studies of biological properties of PolyI: PolyC, started in the 1970s, showed that the drug was a powerful activator of innate immunity and an inducer of tumor cell apoptosis [44]. Promising results have been obtained in clinical studies of PolyI:PolyC as a means of treating seasonal influenza [71], as well as treating malignant tumors of different localizations in adults and children [72][73][74].…”