title: Modulation of protective T cell immunity by complement inhibitor expression on tumor cells.
abstract: Complement-inhibitory proteins expressed on cancer cells can provide protection from antitumor antibodies and may potentially modulate the induction of an immune response to tumor-associated antigens. In the current study, we investigated the consequences of complement inhibitor down-regulation on the effector and inductive phases of an immune response. Stable small interfering RNA-mediated down-regulation of the complement inhibitor Crry on MB49 murine bladder cancer cells increased their susceptibility to monoclonal antibody and complement in vitro. In a syngeneic model of metastatic cancer, the down-regulation of Crry on i.v.-injected MB49 cells was associated with a significant decrease in tumor burden and an increase in the survival of challenged mice. However, monoclonal antibody therapy had no additional benefit. There was an antitumor IgG response, but the response was not effected by Crry down-regulation on inoculated tumor cells. Down-regulation of Crry on MB49 cells resulted in an enhanced antitumor T-cell response in challenged mice (measured by lymphocyte IFN-gamma secretion), and CD8+ T cell depletion of mice prior to injection of MB49 cells completely abrogated the effect of Crry down-regulation on tumor burden and survival. Deficiency of C3 also abrogated the effect of Crry down-regulation on the survival of MB49-challenged mice, indicating a complement-dependent mechanism. These data indicate that complement inhibitors expressed on a tumor cell can suppress a T cell response and that enhancing complement activation on a tumor cell surface can promote protective T cell immunity.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Varela
authors.forename: Masaki
authors.initials: M
authors.lastname: Imai
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Rieko
authors.initials: R
authors.lastname: Ohta
authors.forename: Michelle
authors.initials: M
authors.lastname: Rapisardo
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000502:physiology*; D017463:Receptors, Complement 3b; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D003176:Complement C3; C081470:Cr1l protein, mouse; D018396:Mucin-1; D034741:RNA, Small Interfering; D011951:Receptors, Complement; D017463:Receptors, Complement 3b