Abstract
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.
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Abbreviations
- TLR:
-
Toll-like receptor
- CTL:
-
cytotoxic T lymphocyte
- NK:
-
natural killer
- dsRNA:
-
double-stranded RNA
- TICAM-1:
-
Toll/interleukin-1 receptor domain-containing adaptor molecule-1
- IFN:
-
interferon
- TAM:
-
tumor-associated macrophage
- MDSC:
-
myeloid-derived suppressor cell
- G-MDSC:
-
granulocytic MDSC
- M-MDSC:
-
monocytic MDSC
- TAN:
-
tumor-associated neutrophil
- ROS:
-
reactive oxygen species
- RNS:
-
reactive nitrogen species
- TNF:
-
tumor necrosis factor
- WT:
-
wild type
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Acknowledgements
We are grateful to our laboratory members for their invaluable discussions. We also thank Dr. T Taniguchi (University of Tokyo) for providing IFNAR1−/− mice. This work was supported by JSPS KAKENHI Grant Numbers 24590470 and16K08704, Grants from The Ministry of Health, Labour and Welfare (MHLW) and the Research on Development of New Drugs, the Japan Agency for Medical Research and Development (AMED) (16ak0101010h0005), the Takeda Science Foundation, and the Kato Memorial Bioscience Foundation.
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Shime, H., Matsumoto, M. & Seya, T. Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway. Cell Death Differ 24, 385–396 (2017). https://doi.org/10.1038/cdd.2016.131
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DOI: https://doi.org/10.1038/cdd.2016.131
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