Team Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France.
Department of Biologic Immunology, Hôpital Européen Georges-Pompidou, Assistance Publique Hopitaux de Paris, Paris, France.
Cancer Immunol Res. 2021 Aug;9(8):909-925. doi: 10.1158/2326-6066.CIR-20-0787. Epub 2021 May 26.
The complement system is a powerful and druggable innate immune component of the tumor microenvironment. Nevertheless, it is challenging to elucidate the exact mechanisms by which complement affects tumor growth. In this study, we examined the processes by which the master complement regulator factor H (FH) affects clear cell renal cell carcinoma (ccRCC) and lung cancer, two cancers in which complement overactivation predicts poor prognosis. FH was present in two distinct cellular compartments: the membranous (mb-FH) and intracellular (int-FH) compartments. Int-FH resided in lysosomes and colocalized with C3. In ccRCC and lung adenocarcinoma, FH exerted protumoral action through an intracellular, noncanonical mechanism. FH silencing in ccRCC cell lines resulted in decreased proliferation, due to cell-cycle arrest and increased mortality, and this was associated with increased p53 phosphorylation and NFκB translocation to the nucleus. Moreover, the migration of the FH-silenced cells was reduced, likely due to altered morphology. These effects were cell type-specific because no modifications occurred upon silencing in other FH-expressing cells tested: tubular cells (from which ccRCC originates), endothelial cells (human umbilical vein endothelial cells), and squamous cell lung cancer cells. Consistent with this, in ccRCC and lung adenocarcinoma, but not in lung squamous cell carcinoma, int-FH conferred poor prognosis in patient cohorts. Mb-FH performed its canonical function of complement regulation but had no impact on tumor cell phenotype or patient survival. The discovery of intracellular functions for FH redefines the role of the protein in tumor progression and its use as a prognostic biomarker or potential therapeutic target..
补体系统是肿瘤微环境中一种强大的、可成药的固有免疫成分。然而，阐明补体影响肿瘤生长的确切机制具有挑战性。在这项研究中，我们研究了主要补体调节因子因子 H（FH）影响透明细胞肾细胞癌（ccRCC）和肺癌的过程，这两种癌症中补体过度激活预示着预后不良。FH 存在于两个不同的细胞区室：膜性（mb-FH）和细胞内（int-FH）区室。Int-FH 存在于溶酶体中，并与 C3 共定位。在 ccRCC 和肺腺癌中，FH 通过一种细胞内非经典机制发挥促肿瘤作用。ccRCC 细胞系中 FH 的沉默导致增殖减少，这是由于细胞周期停滞和死亡率增加，这与 p53 磷酸化和 NFκB 易位到细胞核增加有关。此外，沉默 FH 的细胞迁移减少，可能是由于形态改变。这些效应是细胞类型特异性的，因为在其他表达 FH 的细胞中沉默时没有发生变化：管状细胞（ccRCC 来源于这些细胞）、内皮细胞（人脐静脉内皮细胞）和鳞状细胞肺癌细胞。与此一致，在 ccRCC 和肺腺癌中，但不是在肺鳞状细胞癌中，int-FH 在患者队列中预示着不良预后。Mb-FH 发挥其补体调节的经典功能，但对肿瘤细胞表型或患者存活没有影响。FH 细胞内功能的发现重新定义了该蛋白在肿瘤进展中的作用及其作为预后生物标志物或潜在治疗靶点的用途。
