Abstract
Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) cells, independent of malignant cell lysis. Relative to other innate immune agonists, virotherapy provokes selective, TBK1-IRF3 driven innate inflammation that is associated with sustained type-I/III interferon (IFN) release. Despite priming equivalent antitumor T cell quantities, MDA5-orchestrated TBK1-IRF3 signaling, but not NFκB-polarized TLR activation, culminates in polyfunctional and Th1-differentiated antitumor T cell phenotypes. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. Thus, virus-induced MDA5-TBK1-IRF3 signaling in the TME provides PRR-contextualized IFN responses that elicit functional antitumor T cell immunity. TBK1-IRF3 innate signal transduction stimulates eventual function and differentiation of tumor-infiltrating T cells.
Highlights
Activating intra-tumor innate immunity might enhance tumor immune surveillance
We discover that PVSRIPO mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) constituents, macrophages, without overt tumor cell lysis
During pathogen infection, locoregional innate inflammation engages downstream immune responses[10]. It follows that cancertargeting virotherapy and pattern recognition receptor (PRR) agonists must function within the heterogenous and immune-distorted TME to accomplish both oncolysis/cytotoxicity and antitumor immunotherapy
Summary
Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. The molecular mechanisms by which virotherapy empowers immune surveillance, and whether it differs from that of synthetic pattern recognition receptor (PRR) agonists, is not defined Answering these questions is central to the clinical advancement of innate-stimulating immunotherapy. Beyond direct viral lysis of malignant cells, PVSRIPO has a peculiar, non-lethal virus:host relationship with dendritic cells (DCs) that is associated with sustained type-I/III interferon (IFN) secretion; instigating intratumor innate inflammation; and priming antitumor CD8 T cell immunity[7,8,9]. Induced innate immunity is mediated by MDA5dependent, sustained TBK1-IRF3 signaling, is associated with exaggerated type-I/III IFN secretion, and diverges consistently from TLR-initiated NFκB dominant responses. Selective TBK1IRF3 signaling via MDA5 engages systemic, polyfunctional antitumor T cell responses
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