Pharmacological inhibition of caspase-8 limits lung tumour outgrowth

Background and purpose: Lung Cancer is one of the leading causes of Cancer death worldwide. Despite advances in therapy, conventional therapy is still the main treatment and has a high risk of chemotherapy resistance. Caspase-8 is involved in cell death and is a recognized marker for poor patient prognosis.

Experimental approach: To elucidate the role of Caspase-8 in lung carcinoma, we used human samples of non-small cell lung Cancer (NSCLC) and a mouse model of carcinogen-induced lung Cancer.

Key results: Healthy and cancerous NSCLC samples had similar levels of the active form of Caspase-8. Similarly, lung tumour-bearing mice had high levels of the active form of Caspase-8. Pharmacological inhibition of Caspase-8 by z-IETD-FMK robustly reduced tumour outgrowth and this was closely associated with a reduction in the release of pro-inflammatory cytokines, IL-6, TNF-α, IL-18, IL-1α, IL-33, but not IL-1β. Furthermore, inhibition of Caspase-8 reduced the recruitment of innate suppressive cells, such as myeloid-derived suppressor cells, but not of regulatory T cells to lungs of tumour-bearing mice. However, despite the well-known role of Caspase-8 in cell death, the apoptotic cascade (Caspase-3, caspase-9 and Bcl-2 dependent) was not active in lungs of z-IETD-treated tumour-bearing mice, but instead higher levels of the short segment of c-FLIP (c-FLIPs) were detected. Similarly, human healthy lung samples had higher levels of c-FLIPs than cancerous samples.

Conclusions and implications: Our data suggest that Caspase-8 is an important orchestrator of cancer-associated inflammation and the presence of short segment of c-FLIP determines whether Caspase-8 induces tumour proliferation or tumour arrest/regression in the lung.