Complement anaphylatoxins as immune regulators in cancer

Abstract

The role of the complement system in innate immunity is well characterized. However, a recent body of research implicates the complement anaphylatoxins C3a and C5a as insidious propagators of tumor growth and progression. It is now recognized that certain tumors elaborate C3a and C5a and that complement, as a mediator of chronic inflammation and regulator of immune function, may in fact foster rather than defend against tumor growth. A putative mechanism for this function is complement-mediated suppression of immune effector cells responsible for immunosurveillance within the tumor microenvironment. This paradigm accords with models of immune dysregulation, such as autoimmunity and infectious disease, which have defined a pathophysiological role for abnormal complement signaling. Several types of immune cells express the cognate receptors for the complement anaphylatoxins, C3aR and C5aR, and demonstrate functional modulation in response to complement stimulation. In turn, impairment of antitumor immunity has been intimately tied to tumor progression in animal models of cancer. In this article, the literature was systematically reviewed to identify studies that have characterized the effects of the complement anaphylatoxins on the composition and function of immune cells within the tumor microenvironment. The search identified six studies based upon models of lymphoma and ovarian, cervical, lung, breast, and mammary cancer, which collectively support the paradigm of complement as an immune regulator in the tumor microenvironment.

Circulating tumor cell interactions with macrophages: implications for biology and treatment

“…Pf4/CXCL4 has been demonstrated to prevent monocyte apoptosis and to promote macrophage differentiation from peripheral blood monocytes (87)(88)(89). CFD is essential for alternative pathway activation and was found to be identical to the adipokine adipsin which is expressed in monocytes/macrophages (90)(91)(92). VDBP is as precursor of the group-specific component protein-derived macrophage-activating factor (GcMAF) (93).…”

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

“…40,41 Besides regulation of the coagulation system, complement proteins stimulate cancer invasion through enhanced EMT, degradation of ECM by proteases such as MMP-9 and induction of chemotactic stimuli and growth factors. [42][43][44] CFD is essential for alternative pathway activation and was found to be identical to the adipokine adipsin which is expressed in monocytes/macrophages. 45,46 Since the CTC lines were established from patients with advanced SCLC characterized by large number of these cells in the circulation, CFD may be involved in cancer-associated weight loss.…”

Anaphylatoxin C3a: A potential biomarker for esophageal cancer diagnosis

“…It may be hypothesized that C3a plays a key role in promoting esophageal tumorigenesis. As previously reported, anaphylatoxin C3a may contribute to cancer cell immune escape via promoting local immunosuppression (30,31). However, more studies should be conducted to elucidate the mechanisms through which C3a promotes esophageal tumorigenesis.…”