Complement Factor H Autoantibodies Are Associated with Early Stage NSCLC

Abstract

Purpose: To discover diagnostic biomarkers associated with early-stage non-small cell lung cancer (NSCLC), we searched for autoantibodies preferentially present in stage I patients compared with patients with advanced-stage disease. Here we describe an autoantibody against complement factor H (CFH) and this autoantibody's association with early-stage NSCLC.Experimental Design: Immunoblots were used to detect autoantibodies in the sera of stage I NSCLC patients. An autoantibody recognizing a 150 kDa protein was discovered, and the protein was identified by mass spectrometry. The association of the autoantibody with early-stage disease was suggested by the results of immunoblot analysis with sera from 28 stage I patients and 28 stage III/IV patients. This association was confirmed by protein microarray of sera from 125 NSCLC patients of all stages as well as 125 controls matched by age, gender, and smoking history.Results: The immunoreactive protein was identified as CFH. By immunoblot analysis, anti-CFH autoantibody was found in 50% of stage I NSCLC patients and 11% of late-stage NSCLC patients (P = 0.003). By protein microarray analysis, patients with stage I NSCLC had a significantly higher incidence of anti-CFH antibody than those with late-stage NSCLC (P = 0.0051). The percentage of sera with a positive level of CFH autoantibody was 30.4% in stage I, 21.1% in stage II, 12.5% in stage III, 7.4% in stage IV, and 8.0% in the control group.Conclusions: These findings suggest that in patients with NSCLC, CFH autoantibody is a molecular marker associated with early-stage disease. Clin Cancer Res; 16(12); 3226-31. ©2010 AACR.Patients with non-small cell lung cancer (NSCLC) typically present with advanced-stage disease, and almost all will eventually die with metastasis. Even patients classified as having stage I disease have a 5-year survival rate of <60%, suggesting undetected micrometastasis at the time of presentation (1, 2). Unfortunately, attempts to improve outcome through early detection efforts using chest radiographs, sputum cytology, and more recently, low-dose computed tomography (CT) have failed to show a reduction in mortality. New strategies that make use of our continually improving understanding of oncogenesis and the process of metastasis are needed if early detection efforts are to be successful.One approach to early detection is the discovery of novel biomarkers that could not only identify patients with lung cancer, but could assist in appropriate staging. Autoantibodies are one class of potentially useful serum biomarkers as there is a low incidence of cancer-associated autoantibodies in healthy individuals (3). In addition, the autoantibody response elicited against a tumor-associated antigen may elucidate a unique therapeutic target, albeit in a select group of cancer patients. Here we report the discovery of an autoantibody to complement factor H (CFH), one of the complement inhibitory proteins on tumor cells, and show its association with early-stage NSCLC. Materials and Methods Pati...

A Therapeutic Antibody for Cancer, Derived from Single Human B Cells

“…Lung cancer cells were chosen because we originally discovered CFH autoantibodies in lung cancer patients (Amornsiripanitch et al, 2010). In the CDC assay, cells are mixed with antibodies and normal human serum (NHS) as a source of complement, incubated at 37 °C, and cytolysis is measured by lactate dehydrogenase (LDH) release.…”

“…We have been studying the immune response in a distinct group of patients with early stage disease who do not develop metastasis as an approach to developing therapeutic strategies (Amornsiripanitch et al, 2010). Our goal was to identify tumor specific antibodies capable of initiating tumor cell death, while stimulating a durable, long term adaptive immune response.…”

Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos‐ and histology‐related changes in lung cancer

“…However, up-regulation of potential oncogenes were also identified, such as the leukemia associated gene MCL1, the inflammation involved gene PTGS2 (COX2) as well as the lung cancer associated genes NR4A2 and CFH. Inhibition of NR4A2 has been shown to be associated with growth suppression in LKB1 (19p13) null lung tumors and CFH auto-antibodies are associated with early stage NSCLC (Amornsiripanitch et al, 2010;Komiya et al, 2010).…”

Complement Factor H Antibodies from Lung Cancer Patients Induce Complement-Dependent Lysis of Tumor Cells, Suggesting a Novel Immunotherapeutic Strategy

“…The 20 SCRs that comprise CFH are each approximately 60 amino acids long, are arranged head to tail, and contain four cysteine residues forming two disulfide bonds per module (13). We originally detected antibodies to CFH in the sera of NSCLC patients by immunoblot, for which the CFH was reduced and denatured (2). As shown in Fig.…”

“…In a previous report, we demonstrated an association of autoantibodies to complement factor H (CFH) in patients with early-stage, nonmetastatic, non-small cell lung cancer (NSCLC; ref. 2). CFH is one of a class of complement inhibitory factors that protect both normal and tumor cells from attack and destruction by the complement system (3,4).…”