NK cells mediate clearance of CD8+ T cell–resistant tumors in response to STING agonists

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Science Immunology  20 Mar 2020:
Vol. 5, Issue 45, eaaz2738
DOI: 10.1126/sciimmunol.aaz2738

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Priming NK Cells for Tumor Destruction

Tumors with low neoantigen burden and/or diminished class I MHC expression evade CD8+ T cells, but NK cells provide another option to target such tumors for immune elimination. Nicolai et al. used several mouse models to investigate the mechanisms by which intratumoral injection of a cyclic dinucleotide (CDN) agonist for STING potentiated the antitumor activity of NK cells, both in the injected tumor and at a remote, uninjected tumor site. CDN administration induced type I interferons that directly promoted NK cell activation and simultaneously enabled an indirect pathway of activation driven by induction of IL-15 and IL-15Rα on dendritic cells. These findings provide preclinical evidence that amplification of NK-based tumor immunity may offer a valuable adjunct to immunotherapy approaches promoting CD8+ T cell–dependent antitumor responses.


Several immunotherapy approaches that mobilize CD8+ T cell responses stimulate tumor rejection, and some, such as checkpoint blockade, have been approved for several cancer indications and show impressive increases in patient survival. However, tumors may evade CD8+ T cell recognition via loss of MHC molecules or because they contain few or no neoantigens. Therefore, approaches are needed to combat CD8+ T cell–resistant cancers. STING-activating cyclic dinucleotides (CDNs) are a new class of immune-stimulating agents that elicit impressive CD8+ T cell–mediated tumor rejection in preclinical tumor models and are now being tested in clinical trials. Here, we demonstrate powerful CDN-induced, natural killer (NK) cell–mediated tumor rejection in numerous tumor models, independent of CD8+ T cells. CDNs enhanced NK cell activation, cytotoxicity, and antitumor effects in part by inducing type I interferon (IFN). IFN acted in part directly on NK cells in vivo and in part indirectly via the induction of IL-15 and IL-15 receptors, which were important for CDN-induced NK activation and tumor control. After in vivo administration of CDNs, dendritic cells (DCs) up-regulated IL-15Rα in an IFN-dependent manner. Mice lacking the type I IFN receptor specifically on DCs had reduced NK cell activation and tumor control. Therapeutics that activate NK cells, such as CDNs, checkpoint inhibitors, NK cell engagers, and cytokines, may represent next-generation approaches to cancer immunotherapy.

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