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.
Highlights
The complement system is an evolutionarily primordial component of the innate immune response that functions through a series of over 30 coordinated cascading proteins and zymogens to protect the body from invading pathogens [1]
First and foremost, Membrane-bound complement regulatory proteins (mCRPs) act locally in mCRPs in Tumor Development and Immunotherapy the Tumor Microenvironment (TME) to tightly regulate the activation of the complement cascade at various steps
Recent data is showing that mCRPs interact with aspects of the adaptive immune response, where by and large, mCRPs are being shown to downregulate T-cell responses to cancer
Summary
The complement system is an evolutionarily primordial component of the innate immune response that functions through a series of over 30 coordinated cascading proteins and zymogens to protect the body from invading pathogens [1]. The naïve T cells that are stimulated in response to CD55 and CD97 binding are shown to produce cells that behave like Tregs, which would promote tumor progression if expressed in the TME [91] It is not entirely clear whether CD55 is expressed by tumors to help defend against the deleterious effects of complement activation, or whether CD55 expression on tumors is more functionally related to its role as a ligand for CD97 in T-cell activation. An example of the successful use of this strategy can be seen in a study by Gelderman et al where the group designed a bispecific anti-CD55 and anti-Ep-CAM antibody that was able to precisely target and cause C3 deposition in cervical and colorectal carcinomas, which overexpress Ep-CAM [142, 143] These targeted therapies certainly provide an excellent approach to developing safer and more effective anti-cancer therapeutics, though more in-depth clinical studies are needed in order to further categorize potential toxicities of the various mCRP targeting drugs
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