The cGAS/STING pathway is an important part of the DNA sensing machinery and plays an important role in fundamental processes of the anti-tumor immune response. Recently it has been hypothesized that cGAS expression might as well have a pro-tumorigenic role through chronic inflammation. Exposure to asbestos fibers can lead to a long-lasting inflammation of the pleura, which is promoting development of malignant pleural mesothelioma (MPM). The aim of this work was to investigate the expression of cGAS and STING as predictive or prognostic factors for patients with MPM.
We analysed tissue micro arrays (TMAs) with tumor tissue from 190 MPM patients by multiparameter immunofluorescence and multispectral microscopy. We evaluated the expression of cGAS and STING in tumor cells, non-tumor cells and CD8 T cells in chemotherapy naïve and matching treated MPM tissue samples. The different cell phenotypes were assessed for cGAS and STING expression on a single cell level and results were correlated to response to treatment and progression free survival.
A low count of cGAS+ cells before the start of chemotherapy is a favorable prognostic marker for progression free survival. The majority of cGAS+ cells are non-tumor cells followed by tumor cells. After chemotherapy, all cell subtypes showed a significant increase of cGAS+ (p<0.0001) but not STING. In patients who achieved a partial response after chemotherapy, the increases of cGAS+ cells was significantly lower compared to patients with progression of disease (11.8 fold vs. 25.86 fold increase, p=0.022).
Here we show that low cGAS+ expression at baseline is favorable prognostic marker and that the increase of cGAS expression is a negative predictive marker in MPM patients. The possible pro-tumorigenic role for this disease warrants further investivation.
The authors.
Stiftung für angewandte Krebsforschung Zürich Krebsliga des Kantons Zürich.
All authors have declared no conflicts of interest.