Potential marker for success of immunotherapy in the treatment of lung cancer

KRAS is a monomeric G-protein that is of crucial importance in the growth of malignant tumors. KRAS mutated lung cancers often develop in chronically inflamed lungs, especially in heavy smokers. The inflammatory processes promote the growth of tumor cells. The research group has now been able to show that these malignant cells often only produce the strong anti-inflammatory protein A20, which is produced in the body itself, in small quantities and that the life expectancy of the patients is directly related to the expression of this protein. Moll explains: "Both in humans and in animal models, the loss of A20 leads to a reduction in tumor immune surveillance. Tumor cells with small amounts of A20 can evade recognition by the body's own immune system." The result is significantly faster tumor growth.

As part of this study, co-financed by the Cancer Research Initiative of the MedUni Vienna and associated with the Comprehensive Cancer Center Vienna, the research team also found that this is mainly due to an increased sensitivity of tumor cells to the immunomodulating cytokine interferon gamma. In addition, the tumor cells with reduced A20 responded particularly well to immune checkpoint inhibitors, as did patients suffering from melanoma (skin cancer) with a similar gene expression structure.

"With A20 we were able to discover a previously unknown tumor suppressor in lung cancer, the loss of which contributes to the development of this malignant disease as an immune checkpoint," explains co-author Emilio Casanova from the Institute of Pharmacology. Since patients with little A20 expression show only a few tumor-fighting immune cells and accordingly do not express much of the important immune checkpoint molecule PD-L1 in the advanced stage, these patients could be excluded from immunotherapies directed against PD-L1. Because the strength of the expression of this molecule is currently used as a decision-making aid as to whether or not to receive therapy with immune checkpoint inhibitors. "Based on our results and the available data from melanoma patients, we are convinced that we have identified a group of lung cancer patients who would very well benefit from this immunotherapy. Exclusion from such a therapy would significantly reduce the survival rate of those affected."

In another study, the researchers want to find out whether the expression of A20 in the tumor cells can be manipulated in a targeted manner in order to further enhance the effect of immunotherapies. "Still, smoking is the most easily avoidable risk factor for lung cancer. Therefore, on the one hand, laws should be supported that protect the general public from harmful inhalation of smoke, but on the other hand, they should also appeal to personal responsibility to stop smoking altogether," says Moll. Nevertheless, according to the MedUni Vienna expert, it is important that further therapeutic approaches are researched in order to improve the quality of life and survival prognosis of those affected.

Service: Science Translational Medicine

"Downregulation of A20 promotes immune escape of lung adenocarcinomas."
K. Breitenecker, M. Homolya, A. C. Luca, V. Lang, C. Trenk, G. Petroczi, J. Mohrherr, J. Horvath, S. Moritsch, L. Haas, M. Kurnaeva, R. Eferl, D. Stoiber, R. Moriggl, M. Bilban, A. C. Obenauf, C. Ferran, B. Dome, V. Laszlo, B. Győrffy, K. Dezso, J. Moldvay, E. Casanova, H. P. Moll.

DOI: stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.abc3911