Down-regulation of human complement factor H sensitizes non-small cell lung cancer cells to complement attack and reduces in vivo tumor growth.
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.
Ajona
Daniel
D
Division of Oncology, Center for Applied Medical Research, School of Medicine, University of Navarre, Pamplona 31008, Spain.
Hsu
Yi-Fan
YF
Corrales
Leticia
L
Montuenga
Luis M
LM
Pio
Ruben
R
D000818:Animals; D018958:CD55 Antigens / Q000187:drug effects / Q000276:immunology; D018957:CD59 Antigens / Q000187:drug effects / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003167:Complement Activation / Q000235:genetics; D003176:Complement C3 / Q000032:analysis / Q000276:immunology; D015936:Complement C5a / Q000276:immunology; D017242:Complement Factor H / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology*; D051916:Membrane Cofactor Protein / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D034741:RNA, Small Interfering / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D018958:CD55 Antigens; D018957:CD59 Antigens; D003176:Complement C3; D051916:Membrane Cofactor Protein; D034741:RNA, Small Interfering; D015936:Complement C5a; D017242:Complement Factor H