Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+intratumor myeloid cells through the TICAM-1 signaling pathway.
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 CD8α+/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)-αβ 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 CD8α+/CD103+DCs that prime CTLs.
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Hiroaki
H
Shime
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Misako
M
Matsumoto
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Tsukasa
T
Seya
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000950:Antigens, Ly; D039481:CD11b Antigen; D053148:Caspase 3; D053181:Caspase 8; D011070:Poly I-C; D012330:RNA, Double-Stranded; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D053633:Receptor, Interferon alpha-beta; C512612:MAVS protein, mouse; C508032:Ifnar1 protein, mouse; C480309:Ly6G antigen, mouse; C476286:Ticam1 protein, mouse