2. Academic Validation
  3. Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

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

  • Cancer Cell. 2023 May 12;S1535-6108(23)00162-9. doi: 10.1016/j.ccell.2023.04.018.
Xiuting Liu 1,  Graham D Hogg 1,  Chong Zuo 1,  Nicholas C Borcherding 2,  John M Baer 1,  Varintra E Lander 1,  Liang-I Kang 3,  Brett L Knolhoff 1,  Faiz Ahmad 1,  Robin E Osterhout 4,  Anna V Galkin 4,  Jean-Marie Bruey 4,  Laura L Carter 4,  Cedric Mpoy 5,  Kiran R Vij 2,  Ryan C Fields 6,  Julie K Schwarz 7,  Haeseong Park 8,  Vineet Gupta 9,  David G DeNardo 10
Affiliations

Affiliations

  • 1 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 Gossamer Bio, Inc., San Diego, CA, USA.
  • 5 Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 6 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 7 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 8 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 9 Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
  • 10 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: ddenardo@wustl.edu.
PMID: 37236195 DOI: 10.1016/j.ccell.2023.04.018
Abstract

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.

Keywords

CD11b; NF-κB; STING; immunotherapy; pancreatic cancer; tumor-associated macrophages.

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