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

Autor:	Liu X; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Hogg GD; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Zuo C; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Borcherding NC; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA., Baer JM; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Lander VE; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Kang LI; 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., Knolhoff BL; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Ahmad F; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Osterhout RE; Gossamer Bio, Inc., San Diego, CA, USA., Galkin AV; Gossamer Bio, Inc., San Diego, CA, USA., Bruey JM; Gossamer Bio, Inc., San Diego, CA, USA., Carter LL; Gossamer Bio, Inc., San Diego, CA, USA., Mpoy C; Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., Vij KR; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA., Fields RC; 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., Schwarz JK; 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., Park H; 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., Gupta V; Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA., DeNardo DG; 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.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2023 Jun 12; Vol. 41 (6), pp. 1073-1090.e12. Date of Electronic Publication: 2023 May 25.
DOI:	10.1016/j.ccell.2023.04.018
Abstrakt:	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. Competing Interests: Declaration of interests D.G.D. is on the scientific advisory board for Adhaere, 149.Bio, and Gossamer Bio. R.E.O., A.V.G., J.-M.B., and L.L.C. are employees from Gossamer Bio. (Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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