The complement system as a target in cancer immunotherapy.

Malignant cells are part of a complex network within the tumor microenvironment, where their interaction with host cells and soluble mediators, including complement components, is pivotal. The complement system, known for its role in immune defense and homeostasis, exhibits a dual effect on cancer progression. This dichotomy arises from its antitumoral opsonophagocytosis and cytotoxicity versus its protumoral chronic inflammation mediated by the C5a/C5aR1 axis, influencing antitumor T-cell responses.

Complement Terminal Pathway Activation and Intrarenal Immune Response in C3 Glomerulopathy.

Key Points: We evidenced terminal pathway activation (C5b-9 deposits) in most of the glomeruli on kidney biopsy of C3 glomerulopathy. The amount of C5b-9 deposits correlated with disease prognosis in C3 glomerulopathy. Increased terminal pathway activation was found predominantly in a subgroup exhibiting an immuno-fibroblastic signature.

Humoral complementomics - exploration of noninvasive complement biomarkers as predictors of renal cancer progression.

Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC).

Usefulness and analytical performances of complement multiplex assay for measuring complement biomarkers in plasma.

Introduction: The complement system is involved in numerous diseases, through diverse mechanisms and degree of activation. With the emergence of complement targeting therapeutic, simple and accessible tools to evaluate the extent of complement activation are strongly needed.

Methods: We evaluated two multiplex panels, measuring complement activation fragments (C4a, C3a, C5a, Bb, Ba, sC5b9) and intact components or regulators (C1q, C2, C3, C4, C5, FD, FP, FH, FI).

Complement involvement in sickle cell disease.

Sickle Cell Disease (SCD) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells, causing vaso-occlusion. Inflammation is a key component of the pathophysiology of SCD, contributing to the vascular complications and tissue damage. This review is centered on exploring the role of the inflammatory complement system in the pathophysiology of SCD.

Insights into the molecular basis and mechanism of heme-triggered TLR4 signalling: The role of heme-binding motifs in TLR4 and MD2.

Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts of labile heme into the intravascular compartment resulting in the induction of proinflammatory and prothrombotic complications in affected patients. In addition to the relevance of heme-regulated proteins from the complement and blood coagulation systems, activation of the TLR4 signalling pathway by heme was ascribed a crucial role in the progression of these pathological processes. Heme binding to the TLR4-MD2 complex has been proposed recently, however, essential mechanistic information of the processes at the molecular level, such as heme-binding kinetics, the heme-binding capacity and the respective heme-binding sites (HBMs) is still missing.

Basic Mechanisms of Hemolysis-Associated Thrombo-Inflammation and Immune Dysregulation.

Independent of etiology, hemolytic diseases are associated with thrombosis, inflammation and immune dysregulation, all together contributing to organ damage and poor outcome. Beyond anemia and the loss of the anti-inflammatory functions of red blood cells, hemolysis leads to the release of damage-associated molecular patterns including ADP, hemoglobin, and heme, which act through multiple receptors and signaling pathways fostering a hyperinflammatory and hypercoagulable state. Extracellular free heme is promiscuous alarmin capable of triggering oxido-inflammatory and thrombotic events by inducing the activation of platelets, endothelial and innate cells as well as the coagulation and complement cascades.

Hemolysis is associated with altered heparan sulfate of the endothelial glycocalyx and with local complement activation in thrombotic microangiopathies.

The complement system plays a key role in the pathophysiology of kidney thrombotic microangiopathies (TMA), as illustrated by atypical hemolytic uremic syndrome. But complement abnormalities are not the only drivers of TMA lesions. Among other potential pathophysiological actors, we hypothesized that alteration of heparan sulfate (HS) in the endothelial glycocalyx could be important.

Acute Influenza Infection Promotes Lung Tumor Growth by Reprogramming the Tumor Microenvironment.

One billion people worldwide get flu every year, including patients with non-small cell lung cancer (NSCLC). However, the impact of acute influenza A virus (IAV) infection on the composition of the tumor microenvironment (TME) and the clinical outcome of patients with NSCLC is largely unknown. We set out to understand how IAV load impacts cancer growth and modifies cellular and molecular players in the TME.

Oxidized hemoglobin triggers polyreactivity and autoreactivity of human IgG via transfer of heme.

Intravascular hemolysis occurs in diverse pathological conditions. Extracellular hemoglobin and heme have strong pro-oxidative and pro-inflammatory potentials that can contribute to the pathology of hemolytic diseases. However, many of the effects of extracellular hemoglobin and heme in hemolytic diseases are still not well understood.

Evolutionary trajectory of receptor binding specificity and promiscuity of the spike protein of SARS-CoV-2.

SARS-CoV-2 infects cells by attachment to its receptor-the angiotensin converting enzyme 2 (ACE2). Regardless of the wealth of structural data, little is known about the physicochemical mechanism of interactions of the viral spike (S) protein with ACE2 and how this mechanism has evolved during the pandemic. Here, we applied experimental and computational approaches to characterize the molecular interaction of S proteins from SARS-CoV-2 variants of concern (VOC).

C3-dependent effector functions of complement.

C3 is the central effector molecule of the complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will introduce the C3 forms (native C3, C3 [H O], and intracellular C3), the C3 fragments C3a, C3b, iC3b, and C3dg/C3d, and the C3 expression sites. To highlight the important role that C3 plays in human biological processes, we will give an overview of the diseases linked to C3 deficiency and to uncontrolled C3 activation.

Assessment of the breadth of binding promiscuity of heme towards human proteins.

Heme regulates important biological processes by transient interactions with many human proteins. The goal of the present study was to assess extends of protein binding promiscuity of heme. To this end we evaluated interaction of heme with >9000 human proteins.

IgG Subclass-Dependent Pulmonary Antigen Retention during Acute IgG-Dependent Systemic Anaphylaxis in Mice.

Mouse models of active systemic anaphylaxis rely predominantly on IgG Abs forming IgG-allergen immune complexes that induce IgG receptor-expressing neutrophils and monocytes/macrophages to release potent mediators, leading to systemic effects. Whether anaphylaxis initiates locally or systemically remains unknown. In this study, we aimed at identifying the anatomical location of IgG-allergen immune complexes during anaphylaxis.

Autoantibodies against Complement Classical Pathway Components C1q, C1r, C1s and C1-Inh in Patients with Lupus Nephritis.

Autoantibodies against the complement component C1q (anti-C1q) are among the main biomarkers in lupus nephritis (LN) known to contribute to renal injury. C1q, the recognition subcomponent of the complement classical pathway, forms a heterotetrameric complex with C1r and C1s, and can also associate a central complement regulator and C1 Inhibitor (C1-Inh). However, the frequency and the pathogenic relevance of anti-C1r, anti-C1s and anti-C1-Inh autoantibodies remain poorly studied in LN.

Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation.

Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts of cell-free heme intravascularly and consumption of the protective heme-scavenger proteins in plasma. The liberation of heme has been linked to the activation of inflammatory systems, including the complement system, through alternative pathway activation. Here, we investigated the impact of heme on the regulatory function of the complement system.

Test for Measuring Complement Attack on Endothelial Cells: From Research to Bedside.

As part of the innate immune system, the complement system plays a key role in defense against pathogens and in host cell homeostasis. This enzymatic cascade is rapidly triggered in the presence of activating surfaces. Physiologically, it is tightly regulated on host cells to avoid uncontrolled activation and self-damage.

C1q+ macrophages: passengers or drivers of cancer progression.

The omics era made possible the quest for efficient markers for cancer progression and revealed that macrophage populations are much more complex than just the M1/M2 dichotomy. Complement C1q pops up as a marker of a tolerogenic and immunosuppressive macrophage populations in both healthy and tumor tissues, but the specific role of C1q+ tumor-associated macrophages (TAM) is poorly understood. C1q is co-expressed in healthy and tumor macrophages with human leukocyte antigen DR (HLA-DR), Apolipoprotein E (APOE), and mannose receptor C-type 1 (MRC1) (CD206), suggesting a resident origin of this population.

Coagulome and the tumor microenvironment: an actionable interplay.

Human tumors often trigger a hypercoagulable state that promotes hemostatic complications, including venous thromboembolism. The recent application of systems biology to the study of the coagulome highlighted its link to shaping the tumor microenvironment (TME), both within and outside of the vascular space. Addressing this link provides the opportunity to revisit the significance of biomarkers of hemostasis and assess the communication between vasculature and tumor parenchyma, an important topic considering the advent of immune checkpoint inhibitors and vascular normalization strategies.

Complement factor H: a guardian within?

The glomerular endothelium produces the key complement regulator factor H (FH), but its role in the endothelial cells protection and functional integrity is unclear. In this edition of Kidney International, Mahajan et al. demonstrate that the endothelial-intrinsic FH is important for the cytoskeletal architecture, monolayer integrity, proliferation control, metabolism, and inflammatory signaling regulation.