Antibodies to aquaporin-4 in non-small cell lung cancer: a study on 50 patients

Abstract

Neuromyelitis optica (NMO) is an aetiologically heterogeneous chronic inflammatory disorder of the CNS that predominantly affects the optic nerves and spinal cord [1]. NMO is associated with the presence of serum antibodies to aquaporin-4 (AQP4-Ab, also called NMO-IgG), the most abundant water channel in the CNS [2, 3]. Recently, De Santis et al. [4] reported on a patient with AQP4-Ab positive NMO and non-small cell lung cancer (NSCLC). Whether, NMO occurred independently in that patient or was linked to the presence of NSCLC is unknown. However, the association of AQP4-Ab and NSCLC in that case is intriguing, for AQP4 is expressed constitutively in *40% of all NSCLC carcinomas (Warth et al., unpublished observation). AQP4-Ab may thus be produced as a part of the tumour immune response in some cases. We were therefore interested in whether AQP4-Ab seropositive status is common among patients with NSCLC. The lack of neurological disease in the vast majority of NSCLC patients does not a priori preclude AQP4-Ab seropositivity, for the presence of AQP4-Ab in the serum is not sufficient to induce clinical disease on its own as indicated by the fact that AQP4-Ab remains detectable during remission, partly at high titres [5]; AQP4-Ab has also been detected in samples taken already many years prior to disease onset [6]. This indicates that other factors, for instance, disease-specific T cells, raised cytokines, unspecific stimulation by exogenous triggers or damage to the blood brain barrier, might be required to cause AQP4-Ab induced tissue damage. Indeed, in animal models of NMO, passive transfer of AQP4-IgG to mice had no effect unless brain inflammation and disruption of the blood brain barrier is induced [7–9]. Anti-CNS antibodies in the absence of neurological symptoms have also been reported in classical paraneoplastic neurological disorders. Small cell lung cancer (SCLC) associated anti-neuronal antibodies such as anti-Hu, anti-Ri, anti-amphiphysin, and anti-CV2/CRMP5 can be found in up to 16% of SCLC patients without neurological disease [10]. To address the frequency of AQP4-Ab among patients with NSCLC, we tested fifty anonymized serum samples from clinically and pathologically well-defined patients with NSCLC from various TNM stages obtained from a tumour biobank affiliated to the University of Heidelberg S. Jarius, A. Warth and K. P. Wandinger contributed equally.