Polyinosinic-Polycytidylic Acid Limits Tumor Outgrowth in a Mouse Model of Metastatic Lung Cancer

Abstract

Polyinosinic-polycytidylic acid (poly I:C), a TLR3 ligand, is currently being tested in human clinical trials as an adjuvant to anti-cancer vaccines and in combination with other therapies. However, little is known about its activity in established pulmonary metastasis. The aim of our study was to elucidate the effect of poly I:C (1, 10, or 100 μg/mouse) in a mouse model of B16-F10–induced metastatic lung cancer. Lung tumor growth was arrested after a single administration of poly I:C. This was associated with higher influx of mature dendritic cells (DCs), which drove toward a Th1-like, Th17-like, and cytotoxic immune environment. The interference with IFN type I receptor signaling by means of a specific mAb reversed poly I:C-mediated tumor regression due to lower presence of myeloid DCs, cytotoxic DCs (CD11c+CD8+), NKT cells, CD8+ T cells, and Th1-like cytokines. Moreover, the adoptive transfer of poly I:C-activated bone marrow-derived DCs into tumor-bearing mice resulted in activities similar to those of the systemic administration of poly I:C on lung tumor burden. In conclusion, our data prove that poly I:C has potential anti-tumor activity in a mouse model of established pulmonary metastasis. The activation of DCs and the production of IFN type I are responsible for an effective T cytotoxic immune response against metastatic lung cancer progression after poly I:C treatment.

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

“…13 Poly(I:C) has been shown to rapidly induce secretion of inflammatory cytokines and to elicit cytotoxic T-cell responses, resulting in strong anti-tumor effects in pre-clinical models. [14][15][16] As Poly(I:C) has limiting toxicity, several modified versions such as PolyI:PolyC12U 17 and Poly(IC:LC) 18 have been developed to reduce toxicity. Currently, several clinical trials are evaluating the adjuvanticity of Poly(IC:LC) in cancer immunotherapy including recurrent pediatric low grade gliomas and stage IV melanoma (listed at http://clinicaltrials.gov/).…”

INAM Plays a Critical Role in IFN-γ Production by NK Cells Interacting with Polyinosinic-Polycytidylic Acid–Stimulated Accessory Cells

“…Using this model, a previous study reported that NK1.1 + cells and IFN-g have a critical role in the protection of lung metastases (30). Previous studies demonstrated that the IFN-g receptor expressed on host cells, but not on melanoma cells, is important for development of lung metastases (43)(44)(45). Hence, lung metastases are prevented by the IFN-g-inducible immune response following NK cell activation.…”

Dual Role of TLR3 in Inflammation and Cancer Cell Apoptosis

“…Protection conferred by tumor vaccine including Poly(I:C) was mediated by primary and memory CD8+ T cells that has been robustly activated by antigen crosspresenting DC [111][112][113][114][115], and by IFN-I-activated NK cells [115]. Moreover, in a mouse model of established pulmonary metastasis, Poly(I:C) elicited a Th1-like, Th17-like, and cytotoxic immune environment following the activation of DCs and the production of IFN type [116]. Those animal models allowed also to show that combining Poly(I:C) with CD40 signaling dramatically increased the efficacy of mouse tumor vaccine [117,118].…”