The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy

Abstract

It has long been understood that the control and surveillance of tumors within the body involves an intricate dance between the adaptive and innate immune systems. At the center of the interplay between the adaptive and innate immune response sits the complement system-an evolutionarily ancient response that aids in the destruction of microorganisms and damaged cells, including cancer cells. Membrane-bound complement regulatory proteins (mCRPs), such as CD46, CD55, and CD59, are expressed throughout the body in order to prevent over-activation of the complement system. These mCRPs act as a double-edged sword however, as they can also over-regulate the complement system to the extent that it is no longer effective at eliminating cancerous cells. Recent studies are now indicating that mCRPs may function as a biomarker of a malignant transformation in numerous cancer types, and further, are being shown to interfere with anti-tumor treatments. This highlights the critical roles that therapeutic blockade of mCRPs can play in cancer treatment. Furthermore, with the complement system having the ability to both directly and indirectly control adaptive T-cell responses, the use of a combinatorial approach of complement-related therapy along with other T-cell activating therapies becomes a logical approach to treatment. This review will highlight the biomarker-related role that mCRP expression may have in the classification of tumor phenotype and predicted response to different anti-cancer treatments in the context of an emerging understanding that complement activation within the Tumor Microenvironment (TME) is actually harmful for tumor control. We will discuss what is known about complement activation and mCRPs relating to cancer and immunotherapy, and will examine the potential for combinatorial approaches of anti-mCRP therapy with other anti-tumor therapies, especially checkpoint inhibitors such as anti PD-1 and PD-L1 monoclonal antibodies (mAbs). Overall, mCRPs play an essential role in the immune response to tumors, and understanding their role in the immune response, particularly in modulating currently used cancer therapeutics may lead to better clinical outcomes in patients with diverse cancer types.

Keywords: combination therapy; complement cascade; immunotherapy; mCRP; oncology.

Figure 1

How mCRPs regulate the complement cascade: mCRPs CD55, CD46, and CD59 exert a regulatory influence on the complement cascade to prevent complement from becoming overly activated. CD55, CD46, and CD59 are known to exert control on all three pathways of complement activation. CD55, also known as DAF, accelerates the decay of the C3 convertases (C4bC2a and C3bBb) and consequently the C5 convertases into constituent elements and prevents re-association (55). The outcome is destabilization of the C3 and C5 convertases which results in decreased anaphylatoxin (C3a,C4a, C5a) formation, decreased opsonin formation (C3c and iC3b), and prevention of MAC formation. CD46 functions as a cofactor for Factor I in the cleavage of C3b and C4b (not shown), leading to inactivation of both (56). CD59 prevents the polymerization of C9 and insertion of additional C9 molecules into the C5b-9 complex (57). It also directly interferes with pore formation of C5b-8, resulting in inhibition of MAC formation. While the distribution of CD55, Cd46, and CD59 is varied across tissues of the body, they are all found expressed on the surface of various tumor cells where they serve as biomarker for tumor formation.

Figure 2

The interaction of mCRPs with the adaptive immune response: CD46, CD55, and CD59 all have known interactions with the adaptive immune response. This figure summarizes what is currently known about each of their interactions with adaptive responses, specifically T-cell responses. CD46 is known to be expressed on the surface of tumor cells and its binding to a naïve CD4+ T-cell in the presence of a secondary activation stimuli results in IFNγ and IL-2 production. Though initially immuno-stimulatory, as IL-2 accumulates it causes activated CD4+ T-cells to undergo a transformation into a Th1 Regulatory cell that produces high levels of IL-10. Two important aspects of CD55 activity are shown here. First, CD55 on the surface of T-cells are known to interact with CD97 displayed on the surface of Antigen Presenting Cells (APCs). This interaction leads to a shift in T-cell functionality, resulting in T-cells that function like TRegs and produce IL-10. The blockade of CD55 on the surface of T-cells has also revealed the immunosuppressive function of CD55. When CD55 is blocked on both CD4+ and CD8+ naïve T-cells followed by immune stimulation (in vitro) or immunization (in vivo), T-cells are shown to proliferate and to produce increased IFNγ, IL-2, and IL-4 and decreased IL-10 as compared to cells or animals that were untreated. This effect appears to be dependent on the increased levels of C3 and C5 present due to blocked functionality of CD55. In certain circumstances, CD59 is found to be overexpressed on CD4+ T-cells which results in downregulation of CD4+ activity. Accordingly, blockade of CD59 results in enhanced T cell responses consisting of increased cell proliferation, decreased IL-10 production and increased IFNγ production.