Helicase-driven activation of NF{kappa}B-COX2 mediates the immunosuppressive component of dsRNA-driven inflammation in the human tumor microenvironment

Presence of cytotoxic CD8+ T cells (CTL) in tumor microenvironments (TME) is critical for the effectiveness of immune therapies and patients' outcome, while 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 IRF-3, and induce IFNα, ISG-60, and CXCL10 to promote CTL chemotaxis to ex vivo-treated tumors. However, in contrast to SeV and poly I:C, rintatolimod did not activate the MAVS/helicase pathway, thus avoiding NF-κB- and TNFα-dependent induction of COX-2, COX-2/PGE2-dependent induction of IDO, IL-10, 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), while COX-2 inhibition enhanced the response to poly-I:C only. Our data identify the helicase/NF-κB/TNFα/COX-2 axis as the key suppressive pathway of dsRNA signaling in human TME and suggest that selective targeting of TLR3 or elimination of NF-κB/TNFα/COX2-driven suppression may allow for selective enhancement of type-1 immunity.

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