Lung cancer is one of the most common and deadly types of cancer worldwide, and the ability of cancer cells to evade the body’s immune system poses a significant challenge in treating it. A team of Weill Cornell Medicine scientists recently made a significant breakthrough in understanding this process. They discovered a genetic signature that can predict patient survival and identified a key mechanism lung cancer cells use to avoid immune attacks. This groundbreaking discovery could hasten the development of treatments that can circumvent tumor defense mechanisms, increasing the chances of survival for lung cancer patients.

The signaling pathway involving IRE1 and XBP1 is becoming increasingly recognized as a key player in cancer progression and immune system suppression in various types of cancer.

The study, which was published in the journal Nature Communications, involved the analysis of human lung cancer datasets as well as experiments on preclinical models, and it revealed an important mechanism of lung cancer’s ability to evade the immune system. The transcription factor XBP1s was discovered to play a critical role in this evasion by suppressing the anti-tumor activity of surrounding immune cells, promoting tumor survival. This effect is achieved by increasing the production of prostaglandin E2, an immunosuppressive molecule.

According to the findings, XBP1s play an important role in cancer cells’ ability to control the immune environment within lung tumors. Disabling the body’s cancer-fighting abilities can increase their effectiveness.

According to the American Cancer Society, lung cancer is the leading cause of cancer-related deaths in the United States, accounting for more than 130,000 deaths each year. This type of cancer is also very common, with nearly 250,000 new cases diagnosed each year. Unfortunately, the vast majority of these cases are non-small-cell lung cancer (NSCLC), which is frequently diagnosed in its advanced stages.

Recent advances in cancer treatment that aim to neutralize cancer’s immune-suppressive defenses or launch an attack on tumors with specially designed immune cells have shown promising results in other types of cancer but have had limited success in treating non-small cell lung cancer. Cancer experts believe that this failure is due to the presence of additional immune-suppressing mechanisms in non-small-cell lung cancer that have yet to be discovered. As a result, much research is currently being conducted to identify and counteract these additional immune-regulating pathways.

The research looks into the inner workings of the IRE1α-XBP1 arm of the unfolded protein response, which is known to be overactive in many types of cancer. This pathway has previously been linked to tumor growth and spread, as well as the immune system’s ability to fight them. However, its role in Non-Small Cell Lung Cancer was previously unknown.

The Role of IRE1α in Lung Cancer Immune Evasion

  • The study concentrated on a protein known as IRE1, which is known to play a role in stress responses and cell survival.
  • The researchers discovered that knocking out IRE1 in tumor cells delayed tumor growth and extended mouse survival using genetically engineered mouse models of non-small cell lung cancer.
  • Further examination of human Non-small-cell lung cancer tumor samples revealed that the presence of IRE1 was linked to poorer patient outcomes and that the genetic changes caused by knocking out IRE1 in mouse tumors were also present in human tumors.

Further research revealed that removing XBP1s from non-small cell lung cancer cells significantly slows tumor growth by allowing the immune system to launch a more potent attack. The researchers discovered that the presence of XBP1s within tumor cells increases the production of prostaglandin E2, a highly immunosuppressive molecule. This molecule is secreted into the tumor’s microenvironment and significantly reduces the ability of immune cells to fight cancer.

A Potential Target for Therapy

  • The study’s findings suggest that targeting IRE1α-XBP1 could be an effective therapy for lung cancer because it can both slow the progression of the disease and boost the body’s immune response.
  • The researchers also discovered a specific genetic “signature” in mouse tumors caused by IRE1 knockout that could be used as a diagnostic tool to predict patient outcomes and choose the best treatment options.

Looking to the Future

  • The research advances our understanding of the mechanisms that allow lung cancer to evade the immune system. It paves the way for the development of new therapies targeting IRE1 and other key players in this process.
  • The researchers intend to conduct additional studies to validate their findings and investigate the potential of IRE1 as a therapeutic target in human clinical trials.

The study represents a significant advance in cancer research and could lead to the development of new treatments for lung cancer patients.

The researchers also discovered the genetic changes that occur when IRE1 is removed from non-small-cell lung cancer tumors in mice. They discovered that the same genetic patterns in human NSCLC tumors were associated with better patient outcomes. This genetic “signature” could be used as a diagnostic tool in the future to predict treatment success and choose the best course of therapy.


The research revealed a novel mechanism by which lung cancer cells escape detection by the immune system. The research also showed the important role of the IRE1 protein in letting lung cancer cells escape immune system attacks. The study also provides new insights into the genetic changes that occur in lung cancers. These findings could be used as a diagnostic tool in the future to predict treatment outcomes and in choosing the best course of treatment. The study provides important novel information to fight lung cancer and emphasizes the importance of ongoing research in this field.

Article Source: Reference Paper | Reference Article

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Dr. Tamanna Anwar is a Scientist and Co-founder of the Centre of Bioinformatics Research and Technology (CBIRT). She is a passionate bioinformatics scientist and a visionary entrepreneur. Dr. Tamanna has worked as a Young Scientist at Jawaharlal Nehru University, New Delhi. She has also worked as a Postdoctoral Fellow at the University of Saskatchewan, Canada. She has several scientific research publications in high-impact research journals. Her latest endeavor is the development of a platform that acts as a one-stop solution for all bioinformatics related information as well as developing a bioinformatics news portal to report cutting-edge bioinformatics breakthroughs.


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