Researchers have found out why cancer patients with ARID1A gene mutations are more likely to benefit from immunotherapy. They have discovered that ARID1A mutations can attract immune cells that fight cancer into tumors by triggering a response similar to fighting a virus. This discovery could lead to improvements in cancer treatment and the development of new drugs for various types of cancer, such as endometrial, ovarian, colon, gastric, liver, and pancreatic cancers. Immunotherapy has been a game-changer in cancer treatment in recent years. Instead of attacking the tumor itself, immunotherapies work by helping the immune system of patients to better fight their tumors. ThThe impact of immunotherapy on difficult-to-treat cancers has been significant, but it is concerning that less than half of all cancer patients respond to current immunotherapies. There is an urgent need to find biomarkers that can predict which patients will benefit the most. Scientists have recently observed that patients with tumors containing a mutation in the ARID1A gene are more likely to respond positively to immune checkpoint blockade, a type of immunotherapy that keeps cancer-fighting immune cells activated. This discovery has the potential to improve outcomes for certain cancer patients.The Salk Institute researchers wanted to understand the impact of the ARID1A gene mutation on treatment sensitivity in various cancers such as endometrial, ovarian, colon, gastric, liver, and pancreatic cancers. They aimed to determine how clinicians can use this knowledge to personalize cancer treatments for each patient. The findings of their study, published in Cell on May 15, 2024, show that the ARID1A mutation makes tumors responsive to immunotherapy by attracting immune cells that fight cancer into the tumor through an antiviral-like immune response. The researchers propose that this mutation and antiviral immune response could be utilized as a biomarker for predicting treatment outcomes.To better identify suitable patients for specific immunotherapies, such as immune checkpoint blockade, the study suggests using ARID1A as a marker. The research also supports the idea of developing medications that target ARID1A and similar proteins to increase the sensitivity of other tumors to immunotherapy.
Associate Professor Diana Hargreaves, the senior author of the study, believes that this discovery could significantly impact cancer treatment outcomes. She explains, “These cancer patients with ARID1A mutations already exhibit an immune response, so by using immune checkpoint blockade to enhance this response, we can help them internally eradicate their tumors.”
Although it was mentioned in the study, the article does not specify what “it” refers to.Researchers discovered that individuals with ARID1A mutations had a positive response to immune checkpoint blockade, but the exact connection between the two was not clear. In order to clarify this relationship, Salk scientists used mouse models of melanoma and colon cancer with either mutated ARID1A or functional ARID1A.
The study revealed a strong immune response in all animal models with mutated ARID1A tumors, but not in those with functional ARID1A tumors, indicating that the ARID1A mutation was indeed responsible for the response. The researchers also sought to understand the molecular mechanisms behind this.Matthew Maxwell, a graduate student in Hargreaves’ lab, explained the significance of ARID1A in the nucleus for keeping DNA properly arranged. When ARID1A is not functioning properly, loose DNA can escape into the cytosol, triggering an antiviral immune response that can be boosted even further by immune checkpoint blockade. The ARID1A gene is responsible for coding a protein that helps maintain the shape of DNA and keep the genome stable. Mutations in ARID1A can set off a chain of events similar to a Rube Goldberg machine in cancer cells.The presence of functional ARID1A causes DNA to escape into the cytosol. This triggers the activation of the cGAS-STING pathway, which is an antiviral alarm system. Our cells are designed to recognize cytosolic DNA as foreign and activate the cGAS-STING pathway to protect against viral infections. The cGAS-STING pathway then signals the immune system to bring T cells to the tumor and activate them to become specialized cancer-killing T cells.
Each step in this process – ARID1A mutation, DNA escape, cGAS-STING alarm, and T cell recruitment – builds on the previous one, resulting in an increase of cancer-fighting T cells in the tumor.The article discusses how the mutation of the ARID1A gene can promote an anti-tumor immune response. This finding has the potential to be used in selecting patients for immune checkpoint blockade. Additionally, the research suggests that drugs inhibiting ARID1A or its protein complex could further improve immunotherapy in other patients. This information provides a new understanding of how the immune system can be enhanced to fight cancer.Checkpoint blockade is more effective for cancers with ARID1A mutations, according to researchers. This suggests that immunotherapy should be a priority for patients with mutated ARID1A. These findings are a major advancement in customizing cancer treatment and could lead to new therapies that target and inhibit ARID1A and its protein complex.
In the future, the Salk team hopes that its findings will improve patient outcomes for the many cancer types associated with ARID1A mutations. The team plans to explore this clinical translation with collaborators at UC San Diego.
Other authors of the study include Jawoon Yi, Shitian Li, and Samuel.Rivera, Jingting Yu, Mannix Burns, Helen McRae, Braden Stevenson, Josephine Ho, Kameneff Bojorquez Gastelum, Joshua Bell, Alexander Jones, Gerald Shadel, and Susan Kaech of Salk; Marianne Hom-Tedla and Katherine Coakley of Salk and UC San Diego; Ramez Eskander of UC San Diego; and Emily Dykhuizen of Purdue University.
This research received funding from the National Institutes of Health (NCI CCSG P30 014195, T32DK007541, R01 CA228211, R01 CA285867, R01 CA216101, R01 CA240909, R01 AI066232, R21 MH128678, S10-OD023689), National Science Foundation, Howard Hughes Medical Institute, Cancer Research Institute, Pew-Stewart Scholars for Cancer Research.The study was a collaboration between researchers from the Salk Institute for Biological Studies, University of California San Diego, University of California Berkeley, and University of California Irvine. The team also worked with the American Cancer Society and Padres Pedal the Cause.
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