Down-Regulation of Human Complement Factor H Sensitizes Non-Small Cell Lung Cancer Cells to Complement Attack and Reduces In Vivo Tumor Growth

Abstract

Malignant cells are often resistant to complement activation through the enhanced expression of complement inhibitors. In this work, we examined the protective role of factor H, CD46, CD55, and CD59 in two non-small cell lung cancer cell lines, H1264 and A549, upon activation of the classical pathway of complement. Complement was activated with polyclonal Abs raised against each cell line. After blocking factor H activity with a neutralizing Ab, C3 deposition and C5a release were more efficient. Besides, a combined inhibition of factor H and CD59 significantly increased complement-mediated lysis. CD46 and CD55 did not show any effect in the control of complement activation. Factor H expression was knockdown on A549 cells using small interfering RNA. In vivo growth of factor H-deficient cells in athymic mice was significantly reduced. C3 immunocytochemistry on explanted xenografts showed an enhanced activation of complement in these cells. Besides, when mice were depleted of complement with cobra venom factor, growth was recovered, providing further evidence that complement was important in the reduction of in vivo growth. In conclusion, we show that expression of the complement inhibitor factor H by lung cancer cells can prevent complement activation and improve tumor development in vivo. This may have important consequences in the efficiency of complement-mediated immunotherapies.

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

“…As a loading control, samples were stained for β-actin. 35 While fH has been described as contributing to the protection of several solid tumors and tumor cell lines, [19][20][21][36][37][38][39] its involvement in the resistance of CLL cells to CDC has not yet been reported. By contrast, the role of CD55 and CD59 in the context of CLL has been investigated in more detail.…”

Complement Factor H Is Elevated in Bronchoalveolar Lavage Fluid and Sputum from Patients with Lung Cancer

“…We have previously reported that complement factor H is expressed and secreted by many non-small cell lung cancer (NSCLC) tumors (17). Factor H is an inhibitor of complement activation and promotes tumor growth in vivo (18). The aim of the present study is to explore whether factor H levels are detectable in bronchial fluids of lung cancer patients and to evaluate its potential diagnostic usefulness.…”

Rapid Degradation of the Complement Regulator, CD59, by a Novel Inhibitor

“…14 -17). For example, down-regulation of CD59 and complement system factor H allows sensitization of non-small cell lung carcinoma (NSCLC) cells and their elimination via the complement system (18). Further support for this idea comes from studies demonstrating that expression of CD59 and CD55 on NSCLC cells was highly correlated with the histology and prognosis of the disease (9,11).…”