小柯机器人

华盛顿大学医学院David G. DeNardo团队近期取得重要工作进展，他们研究发现CD11b激动剂对STING干扰素信号的环境依赖性激活增强了抗肿瘤免疫力。相关研究成果2023年5月25日在线发表于《癌细胞》杂志上。

据介绍，炎症途径的慢性激活和干扰素的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，但其潜在机制尚不清楚。

研究人员发现，CD11b激动剂通过同时抑制NF-κB信号传导和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。相反，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，其诱导程度取决于肿瘤微环境，并通过细胞毒性疗法放大。使用I期临床研究的组织，研究人员证明GB1275治疗激活了人类肿瘤TAM中的STING和STAT1信号传导。

总之，这些发现为CD11b激动剂提供了潜在的基于机制的治疗策略，并确定了更有可能受益的患者群体。

附：英文原文

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

Author: Xiuting Liu, Graham D. Hogg, Chong Zuo, Nicholas C. Borcherding, John M. Baer, Varintra E. Lander, Liang-I Kang, Brett L. Knolhoff, Faiz Ahmad, Robin E. Osterhout, Anna V. Galkin, Jean-Marie Bruey, Laura L. Carter, Cedric Mpoy, Kiran R. Vij, Ryan C. Fields, Julie K. Schwarz, Haeseong Park, Vineet Gupta, David G. DeNardo

Issue&Volume: 2023-05-25

Abstract: Chronic activation of inflammatory pathways and suppressed interferon are hallmarksof immunosuppressive tumors. Previous studies have shown that CD11b integrin agonistscould enhance anti-tumor immunity through myeloid reprograming, but the underlyingmechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associatedmacrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferongene expression simultaneously. Repression of NF-κB signaling involves degradationof p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction,with the magnitude of induction dependent on the tumor microenvironment and amplifiedby cytotoxic therapies. Using tissues from phase I clinical studies, we demonstratethat GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors.These findings suggest potential mechanism-based therapeutic strategies for CD11bagonists and identify patient populations more likely to benefit.

DOI: 10.1016/j.ccell.2023.04.018

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00162-9

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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