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

当前位置： X-MOL 学术 › Cancer Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity
Cancer Cell ( IF 48.8 ) Pub Date : 2023-05-25 , 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

Affiliation

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.
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.
Gossamer Bio, Inc., San Diego, CA, USA.
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
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.
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.
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.
Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
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.

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.

中文翻译：

CD11b 激动剂对 STING 干扰素信号的环境依赖性激活可增强抗肿瘤免疫

炎症通路的慢性激活和干扰素抑制是免疫抑制性肿瘤的标志。先前的研究表明CD11b整合素激动剂可以通过骨髓重编程增强抗肿瘤免疫，但其潜在机制仍不清楚。在此，我们发现 CD11b 激动剂通过抑制 NF-κB 信号传导并同时激活干扰素基因表达来改变肿瘤相关巨噬细胞 (TAM) 表型。 NF-κB 信号传导的抑制涉及 p65 蛋白的降解，并且与环境无关。相比之下，CD11b 激动剂通过 FAK 介导的线粒体功能障碍诱导 STING/STAT1 通路介导的干扰素基因表达，诱导的程度取决于肿瘤微环境，并通过细胞毒疗法放大。使用 I 期临床研究的组织，我们证明 GB1275 治疗可激活人类肿瘤 TAM 中的 STING 和 STAT1 信号传导。这些发现提出了针对 CD11b 激动剂的潜在基于机制的治疗策略，并确定了更有可能受益的患者群体。

更新日期：2023-05-25

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南