Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

• Published in: Cancer cell Vol. 41; no. 6; pp. 1073 - 1090.e12
• Main Authors: Liu, Xiuting, Hogg, Graham D., Zuo, Chong, Borcherding, Nicholas C., Baer, John M., Lander, Varintra E., Kang, Liang-I, Knolhoff, Brett L., Ahmad, Faiz, Osterhout, Robin E., Galkin, Anna V., Bruey, Jean-Marie, Carter, Laura L., Mpoy, Cedric, Vij, Kiran R., Fields, Ryan C., Schwarz, Julie K., Park, Haeseong, Gupta, Vineet, DeNardo, David G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.06.2023
• Subjects: CD11b; CD11b Antigen - agonists; Humans; Immunotherapy; Interferons; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - immunology; NF-kappa B - metabolism; NF-κB; pancreatic cancer; Signal Transduction; STING; tumor-associated macrophages; Tumor-Associated Macrophages - immunology; NF-κB; STING; pancreatic cancer; CD11b; immunotherapy; tumor-associated macrophages
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.04.018

Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit. [Display omitted] •CD11b agonists activates STING/STAT1 and represses of NF-κB in TAMs•STING/pSTAT1 activation in TAMs enhances anti-tumor T cell immunity•GB1275 increases pSTAT1 and STING in TAMs in patient tumor tissues•Tumor cell death and innate immune agonists synergize with CD11b agonists Liu et al. report that CD11b agonists activate STING/STAT/interferon pathways and represses NF-κB in in vitro systems, pancreatic cancer mouse models, and human tumors. Tumor cell death and innate immune agonists synergize with CD11b agonists, indicating potential mechanism-based therapeutic strategies for translation of CD11b agonist use in cancer patients.