ReviewObstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors
Section snippets
Introduction: complement and its regulation by membrane complement regulatory proteins (mCRPs)
The complement system is a major component of the innate immune system. It efficiently protects the host from pathogenic microorganisms, contributes to immune complex regulation and represents an important link between the innate and the specific immune system (for review, see Walport, 2001a, Walport, 2001b). Complement comprises a group of more than 30 proteins, which participate in a cascade-like activation process, serve as control proteins or act as cellular receptors. Activation of the
Interaction of cancer cells with complement: activation and regulation
From in vivo and in vitro observations described below, there is sufficient basis to propose that certain cancers activate, directly or indirectly, the autologous complement system. Various types of complement abnormalities have been described in cancer patients. Thus, in vivo classical pathway activation was described in patients with chronic lymphatic leukemia (CLL) who have low serum levels of several complement proteins and increased concentrations of circulating C1r–C1s–C1 inhibitor
Expression of mCRP in primary tumors and by tumor cell lines
Numerous studies have been performed on the mCRPs in primary tumors and in tumor cell lines, in an attempt to clarify their significance to cancer immunoresistance. Much data was added since the last review on this subject (Gorter and Meri, 1999). To avoid an extended and laborious listing of many of those studies, their major findings are summarized in Table 1. From this table it is evident that almost all cancers studied express at least one of the mCRPs and many express CD46, CD55 and CD59.
Means to overcome protection by mCRP
The use of anticancer antibodies for treatment of cancer patients has received recently much attention and interest, especially following the clinical and commercial success of mAb, such as rituximab (Rituxan) and trastuzumab (Herceptin) (Carter, 2001, Ross et al., 2003). It is likely that the therapeutic potential of monoclonal antibodies is largely impaired by the mCRPs (Juhl et al., 1997, Treon et al., 2001, Golay et al., 2001). To succeed in tumor eradication with antibody and complement,
Perspectives
mCRPs impose an obvious obstacle to anticancer antibody-based therapy. This obstacle may be overcome by neutralization of mCRP activity as adjuvant therapy. To ensure that the mCRP blockers will not bind to normal tissues and increase their sensitivity to autologous complement, they ought to be conjugated to a tumor-targeting moiety, such as tumor specific antibodies. The finding that even after blocking of the mCRP, some tumors still remained resistant to complement-mediated lysis (Junnikkala
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