The role of complement inhibitors in the immune response to bladder cancer.

摘要

It is believed that many types of tumors protect themselves from the effects of the complement system by upregulating the expression of membrane-bound complement inhibitors on their cell surface. Complement inhibitory proteins expressed on cancer cells can provide protection from anti-tumor antibodies and may modulate the induction of an immune response to tumor-associated antigens. In the current set of studies we investigated: (1) the mechanisms leading to the upregulation of complement inhibitors on tumors from bladder cancer patients, and (2) the consequences of complement inhibitor downregulation on the effector and inductive phases of an immune response to bladder cancer in a syngeneic model of mouse bladder cancer.; Paired samples of tumor and normal tissue from 22 bladder cancer patients were analyzed for expression of MUC1, CD46, CD55 and CD59, and matched serum samples analyzed for anti-MUC1 IgM and IgG levels. MUC1 was upregulated in 86% of tumor samples. CD46 was upregulated in 77%, CD55 in 55% and CD59 in 59% of tumors. Analysis of the relationship between anti-MUC1 antibody levels and complement inhibitor expression revealed a significant correlation between the expression of the complement inhibitors CD46 and CD55 on tumor cells and the presence of IgM and IgG anti-MUC1 antibodies in the serum of bladder cancer patients. Hence, we propose a mechanism where selection of tumor cells with higher expression of complement inhibitors is mediated by antibodies against the tumor antigen MUC1.; In a separate set of studies, stable siRNA-mediated downregulation of the complement inhibitor Crry led to an increase in C3 deposition and complement-mediated lysis of bladder cancer cells in vitro. In vivo studies determined that mice injected i.v. with bladder cancer cells expressing lower levels of Crry had a significant decrease in tumor burden and a significant increase in survival compared to mice inoculated with bladder cancer cells expressing normal levels of Crry. While anti-tumor antibody responses were detected in the mice injected with Crrylow tumor cells, the decreased tumor burden and improved survival was determined to be caused by the enhancement of an anti-tumor T cell response and was dependent, at least in part, on a functional complement system. The current data indicates that the complement system and complement inhibitors play a significant role in the induction and/or enhancement of T cell responses against tumors in a syngeneic model of mouse bladder cancer.