Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma

Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130(F/F) knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130(F/F): Kras(G12D) model, but not parental Kras(G12D) mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130(F/F): Kras(G12D) mice revealed the upregulation of IL-6 and STAT3-target genes compared with Kras(G12D) muscle tissue. These cachectic features of gp130(F/F): Kras(G12D) mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130(F/F): Kras(G12D): Stat3(-/+) or gp130(F/F): Kras(G12D): Il6(-/-)mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130(F/F): Kras(G12D) mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130(F/F): Kras(G12D) mice. Collectively, these preclinical findings identify transsignalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.