A recent study led by researchers at Weill Cornell Medicine has revealed that a protein common in high levels in lung cancer cells controls a major immunosuppressive pathway, allowing lung tumors to evade immune attack. The discovery could help speed up the development of treatments that overcome this tumor defense mechanism and improve outcomes for lung cancer patients.
The study, which was published in Nature Communications, analyzed human lung cancer datasets and performed experiments in preclinical models of lung cancer to show that the transcription factor XBP1s enhances tumor survival by suppressing the anti-cancer activity of neighboring immune cells. The researchers discovered that XBP1s exerts this effect by driving the production of a powerful immunosuppressive molecule, prostaglandin E2.
“We found that XBP1s is part of an important pathway in cancer cells that regulates the local immune environment in lung tumors, and can be disabled to increase anticancer immunity,” said study co-senior author Dr. Vivek Mittal, the Gerald J. Ford-Wayne Isom Professor of Cardiothoracic Surgery and director of the Neuberger Berman Lung Cancer Laboratory at Weill Cornell Medicine.
The study was co-led by Dr. Juan Cubillos-Ruiz, the William J. Ledger, M.D., Distinguished Associate Professor for Infection and Immunology in Obstetrics and Gynecology and co-leader of the Cancer Biology Program at the Meyer Cancer Center at Weill Cornell Medicine. The first author of the study is Dr. Michael Crowley, who completed his doctorate in Dr. Mittal’s laboratory in 2021.
Lung cancer is the leading cause of cancer mortality in the United States, with nearly 250,000 new cases reported every year and over 130,000 deaths, according to the American Cancer Society. The vast majority of cases are non-small-cell lung cancer (NSCLC), which is often diagnosed at an advanced stage of progression.
Treatments that attempt to dismantle cancers’ immune-suppressing defenses or attack tumors with engineered immune cells have shown promise against other cancer types, but have had very limited success against NSCLC. This is believed to be due to the presence of additional, undiscovered immune-suppressing mechanisms.
In this study, the researchers focused on the IRE1α-XBP1 arm of the unfolded protein response, a pathway that is chronically upregulated in many cancers. Prior studies of other tumor types have found evidence that this pathway not only directly promotes the survival and progression of tumors, but also helps to suppress the antitumor activity of nearby immune cells. However, the pathway’s role in NSCLC remained largely unexplored.
The study found that when IRE1α is triggered in cells undergoing stress, it starts producing 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 encoding XBP1s from a large set of human NSCLC samples and found that patients whose tumors had higher XBP1s levels had worse chances of survival. In addition, they showed that knocking out IRE1α or XBP1s in NSCLC-like tumors in mice led to tumor regression and markedly improved survival.
Further investigation revealed that the deletion of XBP1s in NSCLC cells impairs tumor growth mainly by allowing the immune system to attack the tumor much more effectively.
The scientists found that XBP1s, when produced within tumor cells, increases production of the strongly immunosuppressive molecule prostaglandin E2, which is secreted into the tumor microenvironment and effectivel