Date on Master's Thesis/Doctoral Dissertation

8-2011

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Committee Chair

Yan, Jun

Author's Keywords

Complement C5a; Tumor immunology; Tumor microenvironment; C5a concentration; Tumor immunotherapy

Subject

Tumors--Immunological aspects; Tumors--Drug therapy; Tumors--Growth

Abstract

Monoclonal antibodies directed toward tumor associated antigens are FDA approved anticancer reagents used commonly in the clinic. Administered antibodies initiate tumor cell death through several mechanisms. Improving immune mediated mechanisms, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may improve treatment success. However, in many tumors, complement activation and propagation is limited by tumor cell overexpression of complement regulatory proteins (CRPs). Thus, introduction of complement components into the tumor, specifically anaphylatoxin C5a, may provide a key strategy to improve existing, approved anti-tumor treatment. Currently the role of C5a in the tumor remains unclear. The receptor for C5a, C5aR, is expressed predominantly by neutrophils and cells of the innate immune system. The human ovarian adenocarcinoma cell line, SKOV-3, was demonstrated to overexpress CRP CD55 which inhibits the release of C5a. As a result, a SCID xenograft model was established to determine the effect of C5a in the tumor microenvironment. The model allowed study of the effect of C5a on innate immune cells exclusively, as well as the introduction of C5a in the presence of CD55. In vivo and in vitro studies were performed to clarify the controversial role of C5a in the tumor and the effect on innate immune cell phenotype and cytotoxic function. The release of local C5a from tumor cells led to enhanced infiltration of macrophages and NK cells, and neutrophils as related to tumor size. C5a also increased production of pro-inflammatory and tumor cytostatic mediator TGF-~ by infiltrating macrophages. Furthermore, C5a down-regulated the generation of iNOS and arginase by infiltrating cells, tumor cell VEGF and total tumor TNF-a production. In vitro studies provided support of C5a significantly improving cytotoxicity of NK cells against tumor cells, and significantly reducing immunosuppression by infiltrating neutrophils. Importantly, C5a in the tumor caused no major systemic alterations or adverse side effects. The result of local C5a release into the tumor microenvironment had a dramatic effect on tumor growth through the recruitment and activation of innate immune cells. C5a altered phenotypes of infiltrating immune cells toward anti-tumorigenic and improved tumor cell cytotoxicity. Based on the findings of C5a in the SKOV -3 xenograft model in the context of published work involving C5a in the tumor, concentration of local C5a is proposed to be critical in determining its role in tumor progression.

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