Therapeutic intervention with complement and beta-glucan in cancer.
Complement (C) has two major effector systems available for host defense. The membrane attack complex (MAC) generated from components C5-C9 can form membrane-penetrating lesions that lead to cell death by causing a rapid loss of cytoplasmic components. The MAC is only effective against pathogens with outer phospholipid membranes, and cannot kill gram-positive bacteria or yeast whose membranes are protected by cell walls. The most important effector mechanism of C is the opsonization of microbial pathogens with the serum protein C3 that leads to their high avidity attachment to the C3-receptors of phagocytic cells. Pathogens that activate complement are first coated with the C3b fragment of C3, which is rapidly proteolyzed into the iC3b fragment by serum factor I. These iC3b fragments serve to promote the high avidity attachment of the 'iC3b-opsonized' pathogens to the iC3b-receptors (CR3, CD11b/CD18) of phagocytic cells and natural killer (NK) cells, stimulating phagocytosis and/or cytotoxic degranulation. Host cells, including neoplastic tumor cells, have been endowed with natural mechanisms for self-protection against both the MAC and the cytotoxic activation of CR3. This review discusses a novel type of immunotherapy for cancer that uses soluble yeast beta-glucan to override the normal resistance of iC3b-opsonized tumor cells to the cytotoxic activation of phagocyte and NK cell CR3, allowing this important effector mechanism of the C system to function against tumor cells in the same way that it normally functions against bacteria and yeast. Moreover, the cytotoxic activation of beta-glucan-primed NK cell CR3 by iC3b-opsonized tumors is shown to be accompanied by a tumor-localized secretion of the cytokines TNFalpha, IFNalpha, IFNgamma, and IL-6.
Department of Pathology, University of Louisville, KY 40292, USA. gordon.ross@louisville.edu
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D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology*; D005936:Glucans / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy
D019496:Cancer Vaccines; D005936:Glucans; D007155:Immunologic Factors; D003165:Complement System Proteins