Understanding how deadly lung cancers control the local immune system

Northwestern Medicine scientists have discovered how a protein found in a deadly type of lung cancer can control how the immune system responds to the tumor, according to a study published in the Proceedings of the National Academy of Sciences.

Lung cancer is the leading cause of cancer death in the United States, accounting for approximately 1 in 5 cancer deaths, according to the American Cancer Society.

KRAS is one of the most frequently mutated genes in lung cancer and is often linked to treatment resistance, said Lillian Eichner, Ph.D., assistant professor of biochemistry and molecular genetics, senior author of the study. study.

“In our previous work, we reported results showing that the HDAC3 protein is extremely important for lung cancer growth in two different in vivo models of KRAS-induced lung adenocarcinoma,” said Eichner, who is also a member of Robert H. Lurie Comprehensive Cancer. Northwestern University Center. “But a fundamental question remained at the end of this study: Does HDAC3 regulate a genetic program shared between different KRAS-driven lung cancer subsets?”

In the study, Eichner and colleagues cultured several types of KRAS-induced lung cancer cells without HDAC3 to better understand the protein’s effects. Using RNA sequencing, the researchers discovered that HDAC3 in lung tumor cells regulates genes responsible for recruiting T cells, immune-fighting cells that are essential effectors of immunotherapies.

Next, using two mouse models of KRAS-induced lung cancer, the researchers inactivated HDAC3 and observed increased recruitment of T cells into lung tumors.

Finally, the researchers administered a combination therapy of the HDAC3-blocking drug entinostat and the anti-cancer drug trametinib to mice harboring KRAS mutant lung tumors and found that T cells useful in fighting tumors increased in quantity in lung tumors, according to the results, stopping tumor growth.

Together, the findings offer new insights into how KRAS mutant lung tumors evade the immune system, Eichner said.

“Our results provide evidence that HDAC3 within tumor cells themselves is a driver of the immune microenvironment,” Eichner said. “By leveraging the spatial precision facilitated by our powerful model systems, we were able to determine what HDAC3 does specifically within the tumor, which allowed us to discover that HDAC3 in the tumor actively restricts immune recruitment, which would be useful in fighting the tumor.

Building on this discovery, Eichner and his laboratory continue to explore the potential of the combination therapeutic approach which has shown great promise in suppressing tumor growth.

“I intend to continue to explore the potential for clinical application of these results. I hope that this article will help continue to motivate clinical interest in this combination. As a fundamentalist researcher, I am truly fascinated by the underlying mechanisms now that we’ve identified what I think is really important tumor biology,” Eichner explained.