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Complement C4d-specific antibodies for the diagnosis of lung cancer.

ABSTRACT: Development of molecular markers that help to identify high-risk individuals or diagnose indeterminate pulmonary nodules could have a major impact on lung cancer clinical management. In this study, we evaluated the diagnostic potential of a newly-developed ELISA that specifically detects complement C4d. We measured this marker in five independent cohorts of plasma and bronchoalveolar lavage samples from lung cancer patients and controls. In case-control studies, the area under the ROC curve for the diagnosis of lung cancer was 0.82 (95%CI = 0.72-0.92) in plasma samples, and 0.80 (95%CI = 0.69 to 0.90) in bronchoalveolar lavage fluids. In a set of plasma samples from the MILD CT-screening trial, the assay was unable to discriminate between asymptomatic high-risk individuals with or without early stage lung cancer. On the contrary, in two independent cohorts of individuals with indeterminate pulmonary nodules, plasma samples from patients with lung cancer nodules presented higher levels of C4d than those from patients with benign nodules. Using a target population of patients with 8 to 30 mm nodules, the test identified likely benign lung nodules with 84% negative predictive value and 54% positive predictive value, at 89% specificity and 44% sensitivity. In conclusion, the specific determination of C4d may serve as an adjunct to current clinical practice in the diagnosis of indeterminate pulmonary nodules.

SUBMITTER: Ajona D

PROVIDER: S-EPMC5814217 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Complement C4d-specific antibodies for the diagnosis of lung cancer.

Ajona Daniel D Okrój Marcin M Pajares María J MJ Agorreta Jackeline J Lozano María D MD Zulueta Javier J JJ Verri Carla C Roz Luca L Sozzi Gabriella G Pastorino Ugo U Massion Pierre P PP Montuenga Luis M LM Blom Anna M AM Pio Ruben R

Oncotarget 20171226 5

Development of molecular markers that help to identify high-risk individuals or diagnose indeterminate pulmonary nodules could have a major impact on lung cancer clinical management. In this study, we evaluated the diagnostic potential of a newly-developed ELISA that specifically detects complement C4d. We measured this marker in five independent cohorts of plasma and bronchoalveolar lavage samples from lung cancer patients and controls. In case-control studies, the area under the ROC curve for ...[more]

PMID: 29464077

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Project description:BackgroundThere is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments.MethodsWe assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test.ResultsLung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61 ± 0.87 vs 0.16 ± 0.11 µg/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13 ± 2.02 vs 1.86 ± 0.95 µg/mL, P < 0.001; 3.18 ± 3.20 vs 1.13 ± 0.69 µg/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93).ConclusionsComplement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.

Project description:This study investigated the mechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays.This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d- TGP, 25 DSA-/C4d- TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays.The mean sum score of glomerulitis and peritubular capillaritis increased from 0.28±0.78 in IFTA specimens to 0.75±0.85 in DSA-/C4d- TGP specimens, 1.71±1.49 in DSA+/C4d-/TGP specimens, and 2.11±1.74 in CAMR specimens (P<0.001). During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8%) compared to IFTA specimens (8.5%), DSA+/C4d- TGP specimens (14.3%), and DSA-/C4d- TGP specimens (16%) (P=0.01). With use of microarrays, comparison of the gene expression profiles of DSA-/C4d- TGP specimens with glomerulitis + peritubular capillaritis scores > 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT). However, both CAMR and DSA+/C4d- TGP specimens had higher expression of not only QCAT but also IFN-? and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens.These results suggested that DSA+/C4d- TGP biopsy specimens may be classified as CAMR. In contrast, DSA-/C4d- TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.

Project description:BackgroundThe complement system plays an important role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in grafts is controversial. The study aimed to fully investigate the risk factors for PTC C4d+ and analyze its significance in biopsy pathology of kidney transplantation.MethodsThis retrospective study included 124 cases of kidney transplant with graft biopsy and donor-specific antibody (DSA) testing from January 2017 to December 2019 in a single center. The effects of recipient pathological indicators, eplet mismatch (MM), and DSAs on PTC C4d+ were examined using univariate and multivariate logistic regression analyses.ResultsIn total, 35/124 (28%) were PTC C4d+, including 21 with antibody-mediated rejection (AMR), eight with renal tubular injury, three with T cell-mediated rejection, one with glomerular disease, and two others. Univariate analysis revealed that DSAs (P < 0.001), glomerulitis (P < 0.001), peritubular capillaritis (P < 0.001), and human leukocyte antigen (HLA) B eplet MM (P = 0.010) were the influencing factors of PTC C4d+. According to multivariate analysis, DSAs (odds ratio [OR]: 9.608, 95% confidence interval [CI]: 2.742-33.668, P < 0.001), glomerulitis (OR: 3.581, 95%CI: 1.246-10.289, P = 0.018), and HLA B eplet MM (OR: 1.166, 95%CI: 1.005-1.353, P = 0.042) were the independent risk factors for PTC C4d+. In receiver operating characteristic curve analysis, the area under the curve was increased to 0.831 for predicting PTC C4d+ when considering glomerulitis, DSAs, and HLA B eplet MM. The proportions of HLA I DSAs and PTC C4d+ in active antibody-mediated rejection were 12/17 and 15/17, respectively; the proportions of HLA class II DSAs and PTC C4d+ in chronic AMR were 8/12 and 7/12, respectively. Furthermore, the higher the PTC C4d+ score was, the more serious the urinary occult blood and proteinuria of recipients at the time of biopsy.ConclusionsPTC C4d+ was mainly observed in AMR cases. DSAs, glomerulitis, and HLA B eplet MM are the independent risk factors for PTC C4d+.

Project description:Antiphospholipid syndrome (APS) is a chronic and disabling condition characterized by recurrent thrombosis and miscarriages mediated by antibodies against phospholipid-binding proteins (aPL), such as beta2glycoprotein I (β2GPI). Complement is involved in APS animal models and complement deposits have been documented in placenta and thrombotic vessels despite normal serum levels. Analysis of circulating blood cells coated with C4d displays higher sensitivity than the conventional assays that measure soluble native complement components and their unstable activation products in systemic lupus erythematosus (SLE). As C4d-coated blood cell count has been reported to be more sensitive than serum levels of complement components and their activation products in systemic lupus erythematosus (SLE) patients, we decided to evaluate the percentage of C4d positive B lymphocytes (BC4d), erythrocytes (EC4d), and platelets (PC4d) in primary APS patients and asymptomatic aPL positive carriers as marker of complement activation in APS. We assessed by flow cytometry the percentages of BC4d, EC4d, and PC4d in primary APS (PAPS; n. 23), 8 asymptomatic aPL positive carriers, 11 APS-associated SLE (SAPS), 17 aPL positive SLE, 16 aPL negative SLE, 8 aPL negative patients with previous thrombosis, 11 immune thrombocytopenia (ITP) patients, and 26 healthy subjects. In addition, we used an in vitro model to evaluate the ability of a monoclonal anti-β2GPI antibody (MBB2) to bind to normal resting or activated platelets and fix complement. EC4d and PC4d percentages were significantly higher in PAPS and aPL carriers as well as aPL positive SLE and SAPS than in aPL negative controls. The highest values were found in PAPS and in SAPS. The EC4d and PC4d percentages were significantly correlated with serum C3/C4 and anti-β2GPI/anti-cardiolipin IgG. In vitro studies showed that MBB2 bound to activated platelets only and induced C4d deposition. The detection of the activation product C4d on circulating erythrocytes and platelets supports the role of complement activation in APS. Complement may represent a new therapeutic target for better treatment and prevention of disability of APS patients.

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Complement C4d-specific antibodies for the diagnosis of lung cancer.

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Complement C4d-specific antibodies for the diagnosis of lung cancer.

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