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Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b⁺Ly6G⁺ intratumor myeloid cells through the TICAM-1 signaling pathway.

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 CD8?⁺/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)-?? 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 CD8?⁺/CD103⁺ DCs that prime CTLs.

SUBMITTER: Shime H

PROVIDER: S-EPMC5344202 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway.

Shime Hiroaki H Matsumoto Misako M Seya Tsukasa T

Cell death and differentiation 20161111 3

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+ ...[more]

PMID: 27834952

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Project description:ObjectiveImmature CD11b + Gr1+ myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b+Gr1+ myeloid cells.MethodsAll studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti-PD1 mAb. The treatment effect was assessed by a survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess the protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies.ResultsThe depletion of Gr1+ immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. In addition to the adoptive transfer studies, these findings validate the role of immunosuppressive CD11b+Gr1+ myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironments produced recruitment and regulatory factors for immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted primarily by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers' expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found to be the most significantly elevated gene in tumor-primed myeloid cells. The inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression and function in myeloid cells.ConclusionOur study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b + Gr1+ myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in immunosuppressive myeloid cells decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer.

Dataset Information

Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b⁺Ly6G⁺ intratumor myeloid cells through the TICAM-1 signaling pathway.

Publications

Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b<sup>+</sup>Ly6G<sup>+</sup> intratumor myeloid cells through the TICAM-1 signaling pathway.

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