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.

Assessment of the expression of the immune checkpoint molecules PD‐1, CTLA4, TIM‐3 and LAG‐3 across different cancers in relation to treatment response, tumor‐infiltrating immune cells and survival

“…The process of T cell recovery demands the cooperation of the tumor microenvironment, the battlefield between the immune system and tumor, where T cells can be activated persistently to attack the tumor cells. In this battlefield, the interactions between the tumor cells and infiltrating immune cells are critical for the tumor response to immune checkpoint blockade . Notably, the infiltrating immune cells consist of various lymphocytes that can attack the tumor cells or help the tumor cells survive the host immune system.…”

Mast cells and complement system: Ancient interactions between components of innate immunity

“…C1s cleaves C4 into components C4a and C4b, and C2 into C2a and C2b. Binding C4b and C2b then forms C4bC2b, which acts as the classical pathway C3 convertase 14 . Due to historical reasons, C2b used to be called C2a, but in analogy with the alternative pathway convertase C3bBb and the other small cleavage fragments (C3a, C4a, and C5a) the nomenclature has changed so that the small released fragment will be called C2a and the convertase bound component C2b 15 .…”

“…CD46 (membrane cofactor protein, MCP) is expressed by all cells except red blood cells (RBCs). It acts as a cofactor for factor I (C3b/C4b inactivator) in cleaving and inactivating C4b and C3b 1,14 . CD55 (decay‐accelerating factor, DAF) degrades the C3 convertases by displacing C2b or Bb away from them 14 .…”

“…It acts as a cofactor for factor I (C3b/C4b inactivator) in cleaving and inactivating C4b and C3b 1,14 . CD55 (decay‐accelerating factor, DAF) degrades the C3 convertases by displacing C2b or Bb away from them 14 . CD59 (protectin) prevents MAC attack by binding to C8 and C9 to inhibit the insertion of the C9 component into the membrane located C5b‐8 and C5b‐9 complexes 14 .…”

Kaposi’s Sarcoma-Associated Herpesvirus and Host Interaction by the Complement System

“…This cell-bound C3b is short-lived and can either be inactivated by a regulatory mechanism involving several inhibitors or initiate the alternative pathway via interactions with factor B, factor D, and properdin. To prevent complement activation, the human body has several soluble and cell-bound regulatory proteins, such as factor H, CD46, CD55, and CD59 [21,22]. As factor H can bind to sialic acid and other neural or anionic polysaccharides on the cell surface, it can interact with glycoproteins on most mammalian cell surfaces [22].…”