Complement System: Promoter or Suppressor of Cancer Progression?

Abstract

Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.

Keywords: anaphylatoxins; cancer; complement system; immune infiltrate; tumor growth; tumor microenvironment.

Figure 1

The complement system schematic summary. The classical pathway is activated by the binding of the C1 complex to immunoglobulins or endogenous ligand. The lectin pathway is analogous to the classical one but its activation is triggered by the fixation of the MBL-MASP complex to the pathogen surface. The alternative pathway is spontaneously initiated by the tick-over mechanism and can be amplified in case of recognition of an unprotected surface by complement regulators. These pathways will lead to the formation of the C3 convertase, an enzymatic complex able to cleave C3 into the anaphylatoxin C3a and C3b. The assemblage of a C3b molecule to the C3 convertase is at the origin of the C5 convertase. The C5 molecule can then be cleaved into the anaphylatoxin C5a and C5b, the latter initiating the terminal pathway. The complement cascade culminates with the formation of the multimeric Membrane Attack Complex (MAC, C5b-9) leading to cell activation or death. The complement system is very powerful in triggering inflammation, phagocytosis, opsonization or also lysis, therefore it is tightly regulated at each step by soluble regulators (C1 inhibitor, Factor I (FI), C4 Binding Protein (C4BP), Factor H (FH), Properdin (FP) clusterin, vitronectin) or membrane proteins (Complement Receptor 1 (CD35, CR1), Membrane Cofactor Protein (CD46, MCP), Decay acceleration Factor (CD55, DAF), CD59). The figure is created with BioRender.com.

Figure 2

Impact of the complement gene expression on the survival of patients with solid tumors. ACC, adrenocortical carcinoma; BLCA, bladder carcinoma; BRCA, invasive breast carcinoma; CESC, cervical squamous carcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; DLBC, diffuse large B cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe carcinoma; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LGG, lower grade glioma; LUAD, lung adenocarcinoma; LUSC, lung squamous carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma. The figure is created with BioRender.com.

Figure 3

Overview of the complement functions in the context of cancer. In a tumor context, the complement system may impact the immunity, angiogenesis and the phenotype of the tumor cells. Immunity: the same complement proteins may impact several immune cells positively or negatively depending of the model or cancer type. The pro-tumoral activity is mostly involved in the recruitment of immune cells and in the suppression of their anti-tumoral response. The anti-tumoral activity is linked to an improvement of the response to therapy and an increase in the immune cells infiltration. Angiogenesis: depending on the model, the complement proteins may promote or hamper tumor growth by favoring or inhibiting the neoangiogenesis. Tumor cells phenotype: by modulating the signaling pathways Erk1/2, AKT and PI3K the complement proteins stimulate tumor growth. In other models, the modulation of other signaling pathway (WWOX and FAS) by complement proteins favor the apoptosis of tumor cells. The figure is created with BioRender.com.