How Does Complement Affect Hematological Malignancies: From Basic Mechanisms to Clinical Application

Abstract

Complement, as a central immune surveillance system, can be activated within seconds upon stimulation, thereby displaying multiple immune effector functions. However, in pathologic scenarios (like in tumor progression), activated complement can both display protective effects to control tumor development and passively promotes the tumor growth. Clinical investigations show that patients with several hematological malignancies often display abnormal level of specific complement components, which in turn modulates complement activation or deregulated cascade. In the past decades, complement-dependent cytotoxicity and complement-dependent cell-mediated phagocytosis were fully approved to display vital roles in monoclonal antibody-based immunotherapies, especially in therapies against hematological malignancies. However, tumor-mediated complement evasion presents a big challenge for such a therapy. This review aims to provide an integrative overview on the roles of the complement in tumor promotion, highlights complement mediated effects on antibody-based immunotherapy against distinct hematological tumors, hopefully provides a theoretical basis for the development of complement-based cancer targeted therapies.

The Role of Alpha 2 Macroglobulin in IgG-Aggregation and Chronic Activation of the Complement System in Patients With Chronic Lymphocytic Leukemia

“…In hematologic malignancies, C activation can have both protective properties as well as tumor growth promoting effects, both direct and indirect ( 35 ). For example, hematological tumor cells show enhanced expression and surface binding of C regulators such as Factor H, Factor H like protein 1 (FHL-1), Factor H related protein 1 (CFHR1), FHR-4, FHR5, and C4b binding protein (C4BP).…”

“…For example, hematological tumor cells show enhanced expression and surface binding of C regulators such as Factor H, Factor H like protein 1 (FHL-1), Factor H related protein 1 (CFHR1), FHR-4, FHR5, and C4b binding protein (C4BP). These C regulators further display the cofactor activity, which function together with factor I to block C activation at the level of C3 convertase, and lead to C evasion ( 35 ). Similarly to these soluble regulators, the membrane-bound C inhibitors CD46, CD55 and CD59 are up-regulated in various primary tumors and tumor lines to evade the C attack ( 35 ).…”

“…These C regulators further display the cofactor activity, which function together with factor I to block C activation at the level of C3 convertase, and lead to C evasion ( 35 ). Similarly to these soluble regulators, the membrane-bound C inhibitors CD46, CD55 and CD59 are up-regulated in various primary tumors and tumor lines to evade the C attack ( 35 ). Also, the soluble form of the C receptor 1 (CR1), expressed on most leukocytes membranes, is shed into the plasma, where it functions as a powerful C inhibitor.…”

“…Also, the soluble form of the C receptor 1 (CR1), expressed on most leukocytes membranes, is shed into the plasma, where it functions as a powerful C inhibitor. This represents another possible C evasion strategy utilized by leukemia cells ( 35 ).…”

Serum Complement Protein C3a Level is Associated With Anti dsDNA Ab in Systemic Lupus Erythematosus: a Brief Report

“…Upon stimulation, complement can be activated within seconds via three different pathways, thereby displaying multiple immune effector functions in controlling infection and maintaining homeostasis [2,3]. The small activation production C3a and C5a, also called anaphylatoxins, are mainly involved in promoting in ammation, including release of proin ammatory cytokines, degranulation of mast cells, an increase in vascular permeability, smooth muscle cell contraction and chemotaxis of immune cells [4]. However, complement behaves as a "double edged sword".…”