Abstract
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 CFH 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.See article by Daugan et al., p. 891 (36).
Highlights
The complement cascade is part of the innate immune system [1][2]
The mb-Factor H (FH) colocalized with IgG and the NaK ATPase pump by IF (Supplementary Figure S1C,D), suggesting an extracellular location of the membranous FH (mb-FH), corresponding to deposits, which is associated with complement activation [7]
C3 can be cleaved by cathepsin L [21] with the help of FH [37], we found that FH and cathepsin L did not colocalize in the clear cell renal cell carcinoma (ccRCC) tumor sections with the limit of our detection method (Figure 5N)
Summary
The complement cascade is part of the innate immune system [1][2]. Tumors are a complement-rich environment [4] in which numerous cell types, including immune cells [5], endothelial cells [6, 7], fibroblasts [8] and the malignant cells themselves [4, 7] contribute to local production of complement components. Overexpression of FH has protumor effects by hampering C3b opsonization and lytic membrane attack complex (MAC) formation on tumor cells [9,10,11]. Consistent with these observations, injection of a blocking FH antibody reduces lung cancer growth in mice [12]. Spontaneous hepatic tumor formation occurs in aged mice with FH deficiency [14]
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