Complement in Tumourigenesis and the Response to Cancer Therapy

Abstract

In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour microenvironment. These novel discoveries have advanced our understanding of the immunosuppressive mechanisms supporting tumour growth and uncovered potential therapeutic targets. This review discusses the current understanding of complement in cancer, outlining both direct and immune cell-mediated roles. The role of complement in response to therapies such as chemotherapy, radiation and immunotherapy is also presented. While complement activities are largely context and cancer type-dependent, it is evident that promising therapeutic avenues have been identified, in particular in combination therapies.

Lymphoid Organ Proteomes Identify Therapeutic Efficacy Biomarkers Following the Intracavitary Administration of Curcumin in a Highly Invasive Rat Model of Peritoneal Mesothelioma

“…In our data, the fact that no change was observed in parallel in lymph nodes could be explained by the finding that activation of the complement cascade resulted in rapid disappearance of C9 from the plasma and accumulation in the spleen [47]. However, although the reversion induced by curcumin treatment was not complete, a common effect in spleen and lymph nodes was observed for another member of the complement system, C3, consistent with its known role in both the classical and alternative pathways [48]. Regarding transgelin-2, Ma and colleagues have revealed that the gene encoding for this protein belonged to a group of fifteen genes involved in curcumin's therapeutic effect against human tongue cancer [41].…”

Complement System: An Immunotherapy Target in Colorectal Cancer

“…In cancer research, the therapeutic aspects of the complement system emerged as a consequence of unveiling its effect on TME components. Complement-related therapies may represent a promising strategy to overcome the failure of response to immunotherapy in different solid tumors including CRC ( 18 ).…”

“…In the last few years, a limited number of reviews and original studies have discussed the potential use of complement in therapeutics of different cancers ( 17 , 18 , 121 , 122 ). Since the role of the complement system remains controversial, whether it is pro- or anti- tumorigenic, studies suggested suppressing the complement activation as a novel strategy for cancer treatment, probably using C5aR and C3aR blockers ( 25 ).…”

“…Another strategy to boost the complement-mediated cytolysis is through the blockage of the MAC blocker “CD59”, such as that reported in lung cancer using trastuzumab and cetuximab (anti-EGFR) antibodies ( 123 ). In addition, another regulatory protein, CD46 (MPC) is a cofactor for C3b and C4b degradation by factor H, which represents another target for the cancer treatment ( 18 ).…”

“…In view of the recognized role of the complement system in inflammation, some reports have recently advocated complement modulation as a potential immunotherapeutic tool in solid tumors, e.g. melanoma as well as ovarian ( 16 ), lung, breast, and colon cancers ( 17 , 18 ).…”