C-Reactive Protein Induces Immunosuppression by Activating FcγR2B in Pulmonary Macrophages to Promote Lung Metastasis

IF 12.5 1区 医学 Q1 ONCOLOGY
Jun-Rui Feng, Xue Li, Cong Han, Yue Chang, Yu Fu, Gong-Chang Feng, Yutiantian Lei, Hai-Yun Li, Patrick Ming-Kuen Tang, Shang-Rong Ji, Yuzhu Hou, Yi Wu
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Abstract

C-reactive protein (CRP) is a liver-derived acute phase reactant that is a clinical marker of inflammation associated with poor cancer prognosis. Elevated CRP levels are observed in many types of cancer and are associated with significantly increased risk of metastasis, suggesting that CRP could have pro-metastatic actions. Here, we reported that CRP promotes lung metastasis by dampening the anti-cancer capacity of pulmonary macrophages in breast cancer and melanoma. Deletion of CRP in mice inhibited lung metastasis of breast cancer and melanoma cells without significantly impacting tumor growth compared to wildtype mice. In addition, the lungs of CRP deficient mice were enriched for activated pulmonary macrophages, which could be reduced to the level of wildtype mice by systemic administration of human CRP. Mechanistically, CRP blocked the activation of pulmonary macrophages induced by commensal bacteria in a FcγR2B-dependent manner, thereby impairing macrophage-mediated immune surveillance to promote the formation of a pre-metastatic niche in the lungs of tumor-bearing mice. Accordingly, treatment with specific CRP inhibitors activated pulmonary macrophages and attenuated lung metastasis in vivo. These findings highlight the importance of CRP in lung metastasis, which may represent an effective therapeutic target for patients with advanced solid cancers in clinics.
C反应蛋白通过激活肺巨噬细胞中的FcγR2B诱导免疫抑制,促进肺转移
C反应蛋白(CRP)是一种来源于肝脏的急性时相反应物,是与癌症预后不良相关的炎症临床标志物。在许多类型的癌症中都可观察到 CRP 水平升高,并且与转移风险显著增加有关,这表明 CRP 可能具有促进转移的作用。在此,我们报告了 CRP 通过抑制乳腺癌和黑色素瘤肺巨噬细胞的抗癌能力来促进肺转移。与野生型小鼠相比,缺失 CRP 的小鼠可抑制乳腺癌和黑色素瘤细胞的肺转移,而对肿瘤生长无明显影响。此外,CRP缺失小鼠的肺部富含活化的肺巨噬细胞,通过全身注射人CRP可将其减少到野生型小鼠的水平。从机理上讲,CRP以FcγR2B依赖的方式阻断了共生细菌诱导的肺巨噬细胞活化,从而损害了巨噬细胞介导的免疫监视,促进了肿瘤小鼠肺部转移前生态位的形成。因此,用特异性CRP抑制剂治疗可激活肺巨噬细胞并减轻体内肺转移。这些发现强调了CRP在肺转移中的重要性,它可能是临床上晚期实体瘤患者的有效治疗靶点。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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