Title: Does secretory leukocyte proteinase inhibitor (SLPI) promote Th17 inflammation and poor host immune surveillance in malignant pleural mesothelioma (MPM)?
Funder: Medical Research Foundation

Abstract: Malignant pleural mesothelioma (MPM) is a devastating cancer that develops in the pleural cavity and largely caused by asbestos exposure. Average survival stands at 9-12 months from diagnosis with the 5-year survival rates projected to be only 2%. The UK has one of the highest MPM death rate in the world (2500+/year) and the Government is now calling on more medical research for better treatments as there are limited efficient therapies available for MPM. The main choice of treatment is chemotherapy (cisplatin and pemetrexed) which only increases survival by several months. Radiotherapy has minimal success due to the diffuse nature of MPM, hence new therapies are needed. Secretory leukocyte proteinase inhibitor (SLPI) is a multifunctional host defence protein found within the lung environment. It inhibits several proteases including neutrophil elastase and modulates inflammation thereby protecting the lung epithelium from damage during pulmonary disease processes. Recent work has shown SLPI to be upregulated in cancer such as non-small cell lung carcinoma and in pleural effusions from mesothelioma patients. Such elevated levels are associated with more aggressive stages of carcinogenesis, such as metastatic disease. In preliminary experiments, we have observed that SLPI is involved in the up-regulation of interleukin-17 (IL-17), an inflammatory cytokine produced by the CD4+ T helper Th17 cells. Th17 cells are traditionally associated with autoimmunity and chronic inflammation. Increased numbers of Th17 cells have been reported in several malignancies including NSCLC and pleural effusions, and negatively correlated to patient prognosis. Furthermore, up-regulation of IL-17 has been reported in NSCLC, pleural effusions and mesothelioma cell lines and is postulated to play important roles in proliferation, metastases and neo-angiogenesis. However, due to their plasticity, Th17 cells can gradually present with a regulatory T-cell (Treg) phenotype. Tregs are known suppressors of tumour immunoregulation and are prevalent within murine and human mesotheliomas. We have observed augmented IL-17 levels in purified CD3+ T-cells treated with SLPI which is not apparent in the SLPI null mice. Therefore, we hypothesize that the over expression of SLPI may drive increased IL-17 levels from the T-cell population which could lead to worsening prognosis in thoracic cancers such as mesothelioma. We postulate that SLPI-induced Th17 responses and infiltration via IL-17 may programme the MPM environment to be immunosuppressive as a result of IL-17 signalling, increase the incidence of Th17 cells and other cells such as M2 macrophages and Tregs in the tumour environment. Such a setting could promote MPM progression through chronically induced inflammation leading to poor tumour recognition and compromised immunosurveillance. This project will highlight SLPI as a potential immunotherapeutic target for the effective treatment of MPM.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS