Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b(+)Ly6G(+) intratumor myeloid cells through the TICAM-1 signaling pathway #MMPMID27834952
Shime H; Matsumoto M; Seya T
Cell Death Differ 2017[Mar]; 24 (3): 385-396 PMID27834952show ga
PolyI:C, a synthetic double-stranded RNA analog, acts as an immune-enhancing adjuvant that regresses tumors in cytotoxic T lymphocyte (CTL)-dependent and CTL-independent manner, the latter of which remains largely unknown. Tumors contain CD11b(+)Ly6G(+) cells, known as granulocytic myeloid-derived suppressor cells (G-MDSCs) or tumor-associated neutrophils (TANs) that play a critical role in tumor progression and development. Here, we demonstrate that CD11b(+)Ly6G(+) cells respond to polyI:C and exhibit tumoricidal activity in an EL4 tumor implant model. PolyI:C-induced inhibition of tumor growth was attributed to caspase-8/3 cascade activation in tumor cells that occurred independently of CD8alpha(+)/CD103(+) dendritic cells (DCs) and CTLs. CD11b(+)Ly6G(+) cells was essential for the antitumor effect because depletion of CD11b(+)Ly6G(+) cells totally abrogated tumor regression and caspase activation after polyI:C treatment. CD11b(+)Ly6G(+) cells that had been activated with polyI:C showed cytotoxicity and inhibited tumor growth through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS). These responses were abolished in either Toll/interleukin-1 receptor domain-containing adaptor molecule-1 (TICAM-1)(-/-) or interferon (IFN)-alphabeta receptor 1 (IFNAR1)(-/-) mice. Thus, our results suggest that polyI:C activates the TLR3/TICAM-1 and IFNAR signaling pathways in CD11b(+)Ly6G(+) cells in tumors, thereby eliciting their antitumor activity, independent of those in CD8alpha(+)/CD103(+) DCs that prime CTLs.
|Adaptor Proteins, Signal Transducing/deficiency/genetics[MESH]
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Cell+Death+Differ 2017 ; 24 (3): 385-396
