Elsevier

Molecular Immunology

Volume 40, Issues 2–4, September 2003, Pages 109-123
Molecular Immunology

Review
Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors

https://doi.org/10.1016/S0161-5890(03)00112-3Get rights and content

Abstract

Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement- and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. CD46, CD55 and CD35 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the membrane attack complex of complement (MAC). These proteins protect normal tissues from accidental injury by activated complement, but also confer resistance on cancer cells, thereby limiting the effect of complement-fixing monoclonal antibodies. Expression of mCRPs on malignant cells is highly variable, yet there is clear indication that certain tumors express higher mCRP levels than the normal tissue from which they have evolved. mCRP level of expression and cellular location may also vary during malignant transformation and between differentiated and undifferentiated tumors. Neutralizing anti-mCRP mAbs have been used in vitro to elucidate the significance of mCRP expression to the tumor complement resistance phenotype. In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy.

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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