Complement as a Biological Tool to Control Tumor Growth

Abstract

Deposits of complement components have been documented in several human tumors suggesting a potential involvement of the complement system in tumor immune surveillance. In vitro and in vivo studies have revealed a double role played by this system in tumor progression. Complement activation in the cancer microenvironment has been shown to promote cancer growth through the release of the chemotactic peptide C5a recruiting myeloid suppressor cells. There is also evidence that tumor progression can be controlled by complement activated on the surface of cancer cells through one of the three pathways of complement activation. The aim of this review is to discuss the protective role of complement in cancer with special focus on the beneficial effect of complement-fixing antibodies that are efficient activators of the classical pathway and contribute to inhibit tumor expansion as a result of MAC-mediated cancer cell killing and complement-mediated inflammatory process. Cancer cells are heterogeneous in their susceptibility to complement-induced killing that generally depends on stable and relatively high expression of the antigen and the ability of therapeutic antibodies to activate complement. A new generation of monoclonal antibodies are being developed with structural modification leading to hexamer formation and enhanced complement activation. An important progress in cancer immunotherapy has been made with the generation of bispecific antibodies targeting tumor antigens and able to neutralize complement regulators overexpressed on cancer cells. A great effort is being devoted to implementing combined therapy of traditional approaches based on surgery, chemotherapy and radiotherapy and complement-fixing therapeutic antibodies. An effective control of tumor growth by complement is likely to be obtained on residual cancer cells following conventional therapy to reduce the tumor mass, prevent recurrences and avoid disabilities.

Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators

“…cGAMP induces modest reactivation in vitro without affecting cell death. Recent achievements in cancer immunotherapy (24)(25)(26) have raised the possibility that the application of immunotherapeutic approaches to other fields, including HIV research, could promote the clearance of the latent HIV-1 reservoir (6,27,28). To evaluate the abilities of immunostimulatory biologic agents to induce the reactivation of HIV-1 provirus and to selectively induce the death of latently HIV-1-infected cells, we first analyzed the effects of three different agonists of innate immunity-the RIG-I agonist M8, previously characterized by our group (29), and the STING agonists cGAMP and c-di-GMP (the cyclic dinucleotide of GMP)-on HIV-1 reactivation in J-Lat 10.6 cells, an in vitro model of HIV-1 latency that contains a green fluorescent protein (GFP) gene substitution in the Nef open reading frame (ORF) (30).…”

CHD4/NuRD complex regulates complement gene expression and correlates with CD8 T cell infiltration in human hepatocellular carcinoma

“…The involvement of the complement genes in tumorigenesis has been reported in many cancer types. However, the conclusions are contradictory [23], raising the possibility that whether the complement system plays a positive or negative regulatory role in tumorigenesis depends on the cancer type. Since some components of the complement system have been reported to function independent of complement system in cancers [24], another possibility is that these complement genes repressed by the CHD4/NuRD complex, including C4B, may play a regulatory role in cancer progression independent of complement system.…”

Deciphering tissue‐based proteome signatures revealed novel subtyping and prognostic markers for thymic epithelial tumors

“…Further comparison of protein expression profiles between thymoma and TSCC identified several extracellular matrix (ECM) proteins, such as CFD, TIMP1, and VCAN, that are overexpressed in TSCC and involved in complement activation and inflammation process. Complement system was traditionally believed to be associated with recognition of cancer cells and function as an effector to disrupt the cancer cells (Gros et al , ; Kochanek et al , ; Macor et al , ; Potlukova and Kralikova, ; Rambach et al , ; Reis et al , ). However, many recent studies also reported its cancer‐promoting role through continuous inflammation in the tumor microenvironment featured by stromal gathering of growth factors, matrix remodeling proteases, cytokines, and chemokines (de Visser et al , ).…”