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Cancer Res. 2018 Aug 1;78(15):4292-4302. doi: 10.1158/0008-5472.CAN-17-3985. Epub 2018 May 31.

Helicase-Driven Activation of NFκB-COX2 Pathway Mediates the Immunosuppressive Component of dsRNA-Driven Inflammation in the Human Tumor Microenvironment.

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Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Medical Center, Ulm, Germany.
Department of Biomedical Engineering, College of Engineering, Carnegie Mellon University, Pittsburgh, PA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Magee-Women's Research Institute, Ovarian Cancer Center of Excellence, Peritoneal/Ovarian Cancer Specialty Care Center, UPMC Hillman Cancer Center, and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Medicine and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York.
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania.


Presence of cytotoxic CD8+ T cells (CTL) in tumor microenvironments (TME) is critical for the effectiveness of immune therapies and patients' outcome, whereas regulatory T(reg) cells promote cancer progression. Immune adjuvants, including double-stranded (ds)RNAs, which signal via Toll-like receptor-3 (TLR3) and helicase (RIG-I/MDA5) pathways, all induce intratumoral production of CTL-attractants, but also Treg attractants and suppressive factors, raising the question of whether induction of these opposing groups of immune mediators can be separated. Here, we use human tumor explant cultures and cell culture models to show that the (ds) RNA Sendai Virus (SeV), poly-I:C, and rintatolimod (poly-I:C12U) all activate the TLR3 pathway involving TRAF3 and IRF3, and induce IFNα, ISG-60, and CXCL10 to promote CTL chemotaxis to ex vivo-treated tumors. However, in contrast with SeV and poly I:C, rintatolimod did not activate the MAVS/helicase pathway, thus avoiding NFκB- and TNFα-dependent induction of COX2, COX2/PGE2-dependent induction of IDO, IL10, CCL22, and CXCL12, and eliminating Treg attraction. Induction of CTL-attractants by either poly I:C or rintatolimod was further enhanced by exogenous IFNα (enhancer of TLR3 expression), whereas COX2 inhibition enhanced the response to poly-I:C only. Our data identify the helicase/NFκB/TNFα/COX2 axis as the key suppressive pathway of dsRNA signaling in human TME and suggest that selective targeting of TLR3 or elimination of NFκB/TNFα/COX2-driven suppression may allow for selective enhancement of type-1 immunity.Significance: This study characterizes two different poly-I:C-induced signaling pathways in their induction of immunostimulatory and suppressive factors and suggests improved ways to reprogram the TME to enhance the antitumor efficacy of immunotherapies. Cancer Res; 78(15); 4292-302. ©2018 AACR.

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