Nicolai et al. showed that intratumoral injection of cyclic dinucleotides (CDN) – activators of cyclic GMP-AMP synthase-stimulator of type I IFN genes (STING) – induced murine NK cells (independent of CD8+ T cells) to potently reject established syngeneic B2m-/- and MHC-I+ NK-activating ligand+ SC tumors of various tissue types in multiple models. Local CDN injection boosted type I IFN levels systemically, infiltration/activation of NK cells in tumors, and systemic NK cell activation to increase control of distal tumor growth and ex vivo NK cell killing, and acted on NK cells directly and indirectly via DC induction of NK-stimulating IL-15/IL-15Rα.
Contributed by Paula Hochman
ABSTRACT: 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-15Ralpha 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.
Author Info: (1) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Division of Immunology and P
Author Info: (1) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (3) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (6) Aduro Biotech Inc., Berkeley, CA 94710, USA. (7) Aduro Biotech Inc., Berkeley, CA 94710, USA. (8) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. raulet@berkeley.edu.
