Influence of chemotherapeutic treatment on the complement system

The complement system as part of the innate immunity is usually regarded as defence system against intruding pathogens and to aid in the removal of immune complexes. In this regard the complement system attracted interest as effector system in increasing the efficiency of antitumour monoclonal antibodies in cancer research. So far, another function of the complement system, the opsonisation of the body's own apoptotic cells with complement components for efficient phagocytosis has received little attention. In a preliminary study, the neoadjuvant combination chemotherapy epirubicin/docetaxel resulted in distinct quantitative changes in the complement components C3 and C4 in the plasma of breast cancer patients within 24 hours after the initial dose. The first aim of the present thesis was the investigation of complement components as biomarkers for the prediction of response to the initial dose of epirubicin/docetaxel in breast cancer patients. Secondly, the applicability of complement components as general markers for the action of chemotherapeutic agents was analysed. In the first part, plasma samples of 25 breast cancer patients were analysed immediately before and 24 hours after the initial chemotherapeutic dose by two-dimensional differential gel electrophoresis (2D-DIGE). Two protein spots belonging to complement C3 showed a correlation with the response to treatment after six cycles of chemotherapy. This result demonstrates that complement C3 is a potential novel predictive biomarker for epirubicin/docetaxel therapy. In the second part of this thesis, the Jurkat T lymphocyte tumour cell line was treated with six different chemotherapeutic agents and deposition of the initiator molecule of the classical complement pathway C1q and the activation fragment C3d on the tumour cells was analysed by flow cytometry. The analysis revealed that deposition of complement C1q and C3d occurred predominantly on late apoptotic cells with a weak DNA staining signal regardless of which chemotherapeutic agent was used. Furthermore, treatment with the chemotherapeutics oxaliplatin or irinotecan resulted in differences in the extent of complement opsonisation. This was also reflected by a differential phagocytosis of tumour cells treated with the two chemotherapeutic agents. Taken together these results suggest that complement components bind to tumour cells after chemotherapy-induced cell death regardless of the type of drug used. The changes in the complement component pattern found in the plasma of breast cancer patients during chemotherapy might be related to this effect. (author)