Therapeutic intervention with complement and beta-glucan in cancer

Complement (C) has two major effector systems available for host defense. T he membrane attack complex (MAC) generated from components C5-C9 can form m embrane-penetrating lesions that lead to cell death by causing a rapid loss of cytoplasmic components. The MAC is only effective against pathogens wit h outer phospholipid membranes, and cannot kill Gram-positive bacteria or y east whose membranes are protected by cell walls. The most important effect or 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 w ith the C3b fragment of C3, which is rapidly proteolyzed into the iC3b frag ment by serum factor I. These iC3b fragments serve to promote the high avid ity attachment of the 'iC3b-opsonized' pathogens to the iC3b-receptors (CR3 , CD11b/CD18) of phagocytic cells and natural killer (NK) cells, stimulatin g phagocytosis and/or cytotoxic degranulation. Host cells, including neopla stic tumor cells, have been endowed with natural mechanisms for self-protec tion 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 im portant effector mechanism of the C system to function against tumor cells in the same way that it normally functions against bacteria and yeast. More over, the cytotoxic activation of beta-glucan-primed NK cell CR3 by iC3b-op sonized tumors is shown to be accompanied by a tumor-localized secretion of the cytokines TNF alpha, IFN alpha, IFN gamma, and IL-6. (C) 1999 Elsevier Science B.V. All rights reserved.