Complement activation cascade and its regulation: relevance for the response of solid tumors to photodynamic therapy.
The complement system has emerged as a prominent participant in host response elicited following treatment of solid tumors by photodynamic therapy (PDT). Activity of the complement system is tightly controlled by a series of endogenous regulatory proteins. The expression of decay-accelerating factor (DAF), complement-receptor-1-related protein y (Crry), and protectin, which are the three major mouse membrane-bound complement regulatory proteins (mCRPs), was examined following treatment of murine squamous cell carcinomas SCCVII by PDT mediated by the photosensitizer Photofrin. A marked decrease was detected in the expression of all three mCRPs on cancer cells from tumors following PDT, indicating that these cells were made more vulnerable to complement attack. In order to amplify this effect, following PDT mice were injected with antibodies neutralizing either Crry, protectin, or DAF. With anti-Crry and anti-protectin this resulted in increased tumor cure rate compared to PDT alone, while the contrary was observed with PDT plus anti-DAF combination (presumably owing to additional role of DAF in T cell signaling). Further examination including other complement regulatory proteins showed that combining antitumor PDT with antibody-mediated neutralization of factor H (soluble negative complement regulator) or injection of properdin (positive complement regulator) increased the cure rates of PDT-treated tumors. The use of various agents promoting complement activity appears promising for employment as adjuvants to PDT.
Korbelik
Mladen
M
British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3. mkorbelik@bccrc.ca
Cecic
Ivana
I
D000818:Animals; D018958:CD55 Antigens / Q000235:genetics; D018957:CD59 Antigens / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D003167:Complement Activation / Q000187:drug effects*; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010778:Photochemotherapy / Q000379:methods*; D011951:Receptors, Complement / Q000235:genetics; D017463:Receptors, Complement 3b
D018958:CD55 Antigens; D018957:CD59 Antigens; C081470:Cr1l protein, mouse; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017323:Dihematoporphyrin Ether