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Scientists detail the main mechanism lung cancer uses to evade the immune system’s attack


Scientists detail the main mechanism lung cancer uses to evade the immune system's attack

Cancer cells undergo endoplasmic reticulum stress. Credits: Ella Marshchenko (2018)

According to a study led by researchers at Weill Cornell Medicine, a protein commonly found at high levels in lung cancer cells controls a key immunosuppressive pathway that allows lung tumors to grow. Avoid attack by the immune system. This finding could spur the development of treatments that bypass this tumor defense mechanism and improve outcomes for lung cancer patients.

In the study that appeared on January 9, natural communicationThe researchers analyzed human lung cancer data sets and performed experiments in preclinical lung cancer models to show that the transcription factor XBP1s enhances tumor exists by inhibiting the antitumor activity of neighboring immune cells. They found that XBP1 exerts this effect by promoting the production of a powerful immunosuppressive molecule, prostaglandins E2.

“We found that XBP1s is part of an important pathway in cancer cells modulate the local immune environment in lung tumorstudy co-author Dr. Vivek Mittal, Gerald J. Ford-Wayne Isom Professor of Cardiovascular Surgery and Director of the Neuberger Berman Lung Cancer Laboratory at Weill Cornell Medicine.

The study’s other senior co-authors are Dr. Juan Cubillos-Ruiz, William J. Ledger, MD, Distinguished Associate Professor of Infection and Immunology in Obstetrics and Gynecology and co-leader of the Cancer Biology Program at Meyer Cancer Center at Weill Cornell Medicine. The first author is Dr Michael Crowley, who completed his PhD at Dr Mittal’s lab in 2021.

According to the American Cancer Society, there are nearly 250,000 new cases of lung cancer each year and more than 130,000 lung cancer deaths, making this form of cancer the leading cause of cancer death in the country. The majority of cases are of the non-small cell lung cancer (NSCLC) type, which is usually diagnosed at an advanced stage.

Newer treatments that attempt to disrupt cancer’s immunosuppressive defenses or attack tumors with engineered immune cells have shown great promise against other types of cancer. other letters, but with very limited success with NSCLC. Cancer researchers believe this is due to additional, unexplored immunosuppressive mechanisms of NSCLC. Much current research aims to explore and seek to disrupt these additional regulatory pathways.

In the study, the researchers focused on the IRE1α-XBP1 arm of the unfolding protein response, a pathway that is frequently downregulated in many cancers. Previous studies on other tumor types have found evidence that this pathway not only directly promotes tumor survival and progression, but also helps block the anti-tumor activity of cells nearby immunity. However, the role of the pathway in NSCLC remains largely unexplored.

When IRE1α is activated in cells under stress, it initiates the production of XBP1, a multifactorial 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 XBP1 from a large subset of human NSCLC samples listed in national databases and found evidence that patients with tumors had Higher levels of XBP1 have a lower chance of survival. Consistent with that finding, they showed that knockdown of IRE1α or XBP1 in murine NSCLC-like tumors led to tumor regression and significantly improved survival.

Further investigation revealed that deletion of XBP1 in NSCLC cells impairs tumor growth primarily by allowing the immune system to attack the tumor much more effectively. The scientists found that XBP1s, when produced in tumor cells, increases the production of a potent immunosuppressive molecule called prostaglandin E2, which is secreted into the tumor microenvironment, where It effectively blocks the anti-cancer activity of immune cells.

The findings suggest that inactivation of IRE1α-XBP1 could be a good therapeutic strategy for NSCLC and may work particularly effectively when combined with other immunotherapies.

“Targeting IRE1α-XBP1 could be a very useful bidirectional therapeutic approach that helps control lung cancer progression while also inducing protective immunity,” said Dr. anti-tumor”.

Dr Mittal, who is also a member of the Meyer Cancer Center, said: “We are currently very interested in finding ways to target an IRE1α inhibitor drug selectively at tumor cells. .

As part of the study, the researchers also mapped the “signature” of gene activity induced by knocking out IRE1α in mouse NSCLC tumors. They found that the presence of this same gene signature in human NSCLC tumors better predicts patient survival. They say a clinical trial based on this marker could be useful in the future to predict outcomes and select optimal treatments.

More information:
Michael JP Crowley et al, Tumor intrinsic IRE1α signaling controls protective immunity in lung cancer, natural communication (2023). DOI: 10.1038/s41467-022-35584-9

quote: Scientists detail key mechanism lung cancer uses to evade immune system attack (2023, January 10) retrieved January 10, 2023 from https:// medicalxpress.com/news/2023-01-scientists-major-mechanism-lung-Cancers.html

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