Abstract
Pattern recognition receptors (PRRs) are germline-encoded host sensors of the innate immune system. Some human cancer cells have been reported to express PRRs. However, nucleic acid sensors in human cancers have not been studied in detail. Therefore, we systematically analyzed the expression, molecular cascade, and functions of TLR3, RIG-I, MDA5, LGP2, cGAS, and STING in human cancer cells. TLR3, TRIF, RIG-I, MDA5, LGP2, and MAVS were expressed in 22 cell lines. The majority of cell lines responded to only RIG-I ligands 5′-ppp-dsRNA, Poly(I:C)-HMW, Poly(I:C)-LMW, and/or Poly(dA:dT), as revealed by IRF3 phosphorylation and IFN-β secretion. IFN-β secretion was inhibited by RIG-I and MAVS knockdown. cGAS and STING were co-expressed in 10 of 22 cell lines, but IFN-β secretion was not induced by STING ligands ISD, HSV60, VACV70, Poly(dG:dC), and 3′3′-cGAMP in cGAS and STING intact cell lines. Further experiments revealed that the cGAS–STING pathway was activated, as revealed by TBK1 and IRF3 phosphorylation and IFN-β and ISG mRNA expression. These results suggest that human epithelial cancer cells respond to cytosolic RNA through the RIG-I–MAVS pathway but only sense cytosolic DNA through the cGAS–STING pathway. These findings are relevant for cancer immunotherapy approaches based on targeting nucleic acid receptors.
Highlights
Pattern recognition receptors (PRRs) are germline-encoded host sensors of the innate immune system that detect pathogen-associated molecular patterns and self-tissue damage-associated molecular patterns
The results showed that TLR3, TRIF, RIG-I, MDA5, laboratory of genetics and physiology 2 (LGP2), and MAVS, which were reported to be expressed in the A549 cell line, were expressed in all these cells lines at both the mRNA and protein levels (Figures 1A,B,D), indicating that the TLR–TRIF and RIG-I-like receptors (RLRs)–MAVS pathways are constitutively intact in all cancer cells
We report that TLR3, TRIF, RIG-I, MDA5, LGP2, and MAVS were expressed in/on all 22 human epithelial cancer cell lines studied, but only cytosolic 5 -ppp-dsRNA, Poly(I:C)HMW, Poly(I:C)-LMW, and/or Poly(dA:dT) could induce IFN-β secretion via the RIG-I–MAVS–IRF3 signaling pathway in most of the cell lines
Summary
Pattern recognition receptors (PRRs) are germline-encoded host sensors of the innate immune system that detect pathogen-associated molecular patterns and self-tissue damage-associated molecular patterns. RLRs comprise three members: RIG-I (DDX58), MDA5 (IFIH1), and laboratory of genetics and physiology 2 (LGP2; DHX58) (Yoneyama et al, 2015) These RLRs share a DExD/H-box RNA helicase domain and a C-terminal domain, both of which are required for dsRNA detection, while RIG-I and MDA5, but not LGP2, have an N-terminal caspase recruitment domain for interaction with MAVS and downstream signaling (Kawai et al, 2005; Meylan et al, 2005; Seth et al, 2005; Xu et al, 2005; Yoneyama et al, 2005). CGAMP binds to STING and mediates the activation of TBK1 and IRF3 to initiate IFN-β secretion (Wu et al, 2013) These findings have translated into the development of new adjuvants for the generation of vaccines and new immunotherapies for cancer that can reverse anti-PD1/anti-PD-L1 resistance by converting “cold tumors” into “hot tumors” (Fu et al, 2015)
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