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
  • 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: [email protected].
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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