A protein commonly found in high levels in lung cancer cells controls a key immunosuppressive pathway that allows lung tumors to evade immune attack, according to a study led by researchers at Weill Cornell Medicine.
This discovery could accelerate the development of therapies that overcome this tumor defense mechanism and improve outcomes for lung cancer patients.
In the study9 in Nature Communications, researchers analyzed human lung cancer datasets and conducted experiments in preclinical models of lung cancer to show that the transcription factor XBP1s promotes tumor survival by suppressing the anticancer activity of neighboring immune cells. They discovered that XBP1s exert this effect by driving the production of a powerful immunosuppressive molecule, prostaglandin E2.
“We found that XBP1s are part of an important pathway in cancer cells that regulates the local immune environment in lung tumors, and can be inactivated to increase anticancer immunity,” said study co-author Vivek Mittal, Gerald J. Ford-Wayne. Isom Professor of Cardiothoracic Surgery and Director of the Neuberger Berman Lung Cancer Laboratory at Weill Cornell Medicine.
The other co-author of the study is Juan Cubilos-Ruiz, Professor William J. Cornell Medicine. The first author is Michael Crowley, who completed his PhD at Metallurgical Laboratory in 2021.
There are approximately 250,000 new cases of lung cancer each year in the United States, and more than 130,000 lung cancer deaths.According to the American Cancer Society, this type of cancer is the leading cause of cancer deaths in the country. Non-small cell lung cancer (NSCLC), which is often diagnosed at an advanced stage of progression, comprises the vast majority of cases.
Newer therapies that attempt to dismantle cancer’s immunosuppressive defenses or attack tumors with engineered immune cells have shown promising results against other cancers, but have had very limited success against small cell carcinomas. Cancer researchers believe that this is due to additional, undiscovered immunosuppressive mechanisms in NSCLC. Much research now aims to uncover and find ways to unravel these additional regulatory pathways.
In the study, the researchers focused on the IRE1α-XBP1 arm of the unfolded protein response, a pathway that is chronically downregulated in many cancers. Previous studies of other tumor types have found evidence that this pathway not only directly promotes survival and progression of tumors, but also helps suppress the antitumor activity of nearby immune cells. However, the role of the pathway in NSCLC has remained largely unexplored.
When IRE1α is switched on in cells under stress, it initiates the production of XBP1s, a multitasking transcription factor that controls the expression of diverse gene programs in a context-specific manner. The researchers analyzed the expression levels of the gene that encodes XBP1s from a large cohort of human NSCLC samples classified in a national database and found evidence that patients with higher levels of XBP1s had worse chances of survival. Consistent with this finding, they showed that knocking out IRE1α or XBP1s in NSCLC-like tumors in mice resulted in tumor regression and significantly improved survival.
Further investigation revealed that deletion of XBP1s in NSCLC cells impairs tumor growth mainly by allowing the immune system to attack the tumor more effectively. The scientists found that XBP1s, when produced within cancer cells, increases the production of a powerful immunomodulatory molecule called prostaglandin E2, which is secreted into the tumor microenvironment where it effectively suppresses the anti-cancer activity of immune cells.
The results suggest that inactivation of IRE1α-XBP1s may be a good treatment strategy for NSCLC and may work particularly well in combination with other immunotherapy approaches.
“Targeting IRE1α-XBP1 could represent a highly beneficial two-pronged therapeutic approach that controls lung cancer progression while inducing protective anti-tumor immunity,” said Cubilos-Ruiz.
“We are now very interested in finding ways to selectively target IRE1α to cancer cells,” said Mittal, who is also a member of the Meyer Cancer Center.
As part of the study, the researchers also mapped the “signature” of gene activity resulting from knocking out IRE1α in the tumors of NSCLC mice. They found that having the same genetic signature in human NSCLC tumors predicted better patient survival. They said that a clinical test based on this signature may be useful, in the future, for predicting outcomes and selecting optimal treatments.
Dr. Juan Cubilos-Ruiz is Scientific Advisor on NextRNA Therapies and Biologic Solutions for Autoimmune and holds patents on IRE1α modulation for disease treatment.
Jim Schnabel is a freelance writer at Weill Cornell Medicine.