Functions of S100A8 in lung cancer

Abstract

S100A8 is an anti-inflammatory oxidant scavenger protein that induces IL-10 in airway epithelial cells in normal lungs following inhalation. These mechanisms contribute to its ability to attenuate endotoxin-induced acute lung injury by suppressing proinflammatory mediator induction. Sustained chronic inflammation promotes activation of myeloid-derived suppressor cells (MDSC) to reduce T cell surveillance by producing toxic reactive oxygen species and nitric oxide, and depleting the essential nutrient, arginine. MDSC accumulation facilitates tumour progression and is associated with reduced survival in lung cancer. S100A8 is upregulated in human lung cancer and the associations of S100 proteins with MDSC suggest a potential immunomodulatory role. We proposed that the anti-inflammatory and antioxidative properties of S100A8 improved outcomes in lung cancer. Remarkably, repeated S100A8 inhalation prolonged survival by up to 40% in mice implanted with orthotopic lung cancer (from 19±1 to 27±1 days). Tumour-bearing mice treated with S100A8 harvested at earlier time points were compared with vehicle-treated controls to identify potential changes in the microenvironment. At mid-point of survival, S100A8 significantly suppressed key cytokines that promote MDSC expansion and activation, with concomitant reduced MDSC numbers in lungs and spleen. Importantly, S100A8 also increased CD4 and NK-T cell numbers in these organs, suppressed nitrite levels and selectively enhanced activities of key antioxidant enzymes in lungs. S100A8 also upregulated thioredoxin reductase activity in lungs 3 days post-inhalation. Results suggest that S100A8 created a favourable microenvironment for effector T cell recruitment and function. Lung cancer is generally associated with poor prognosis and with limited treatment options, and S100A8 may enhance immunoprotection. Its delivery in combination with currently-available treatments may improve clinical outcomes.