ARID1A gene mutation makes tumors sensitive to immunotherapy

Immunotherapy has revolutionized cancer treatment in recent years. Instead of targeting tumors directly, immunotherapy directs patients’ immune systems to attack tumors more effectively. This is particularly effective for some hard-to-treat cancers. However, less than half of all cancer patients respond to current immunotherapies, creating an urgent need to identify biomarkers that can predict which patients are most likely to benefit from treatment.

Recently, scientists have noticed that patients whose tumors have a mutation in the ARID1A gene are more likely to respond positively to immune checkpoint blockade, a type of immunotherapy that works by keeping cancer-fighting immune cells activated.

Because the ARID1A gene mutation is present in many cancers, including endometrial, ovarian, colorectal, gastric, liver and pancreatic cancers, Salk Institute researchers wondered how it might contribute to treatment sensitivity and how clinicians could use this information to personalize cancer treatment for each patient.

Their new study, published in the journal Cell, shows that the ARID1A mutation makes tumors sensitive to immunotherapy by recruiting cancer-fighting immune cells to the tumor through an antiviral-like immune response.

The researchers suggest that this mutation and the antiviral immune response could be used as a biomarker to better select patients for specific immunotherapies, such as immune checkpoint blockade. These findings also encourage the development of drugs that target ARID1A and related proteins to make other tumors more sensitive to immunotherapy.

"This could really change the outcome of cancer treatment for patients," said Associate Professor Diana Hargreaves, senior author of the study. "Patients with the ARID1A mutation already have an immune response, so all we need to do is boost that response with immune checkpoint blockade to help them destroy their tumours from the inside."

Although it was known that people with ARID1A mutations responded well to immune checkpoint blockade, the exact connection between the two remained unclear. To shed light on the mechanism, scientists at the Salk Institute used mouse models of melanoma and colorectal cancer with both the ARID1A mutation and functional ARID1A.

Source: Cell (2024). DOI: 10.1016/j.cell.2024.04.025

The team observed a robust immune response in all models with the ARID1A mutation, but not in those where ARID1A was functional, supporting the idea that the ARID1A mutation is indeed driving this response. But how does this work at the molecular level?

"We found that ARID1A plays an important role in the nucleus by maintaining proper DNA organization," says Matthew Maxwell, first author of the study and a graduate student in the Hargreaves lab. "Without functional ARID1A, free DNA can be excised and released into the cytosol, activating a desirable antiviral immune response that can be enhanced by immune checkpoint blockade."

The ARID1A gene codes for a protein that helps regulate the shape of our DNA and maintain genome stability. When ARID1A mutates, it sets off a Rube Goldberg-like chain of events in cancer cells.

First, the lack of functional ARID1A results in DNA being released into the cytosol. The cytosolic DNA then activates an antiviral alarm system, the cGAS-STING pathway, because our cells are adapted to mark any DNA in the cytosol as foreign to protect against viral infections. Ultimately, the cGAS-STING pathway engages the immune system to recruit T cells to the tumor and activate them into specialized cancer killer T cells.

At each step, dependent on the previous one, this chain of events—ARID1A mutation, DNA escape, cGAS-STING alarm, T-cell recruitment—leads to an increase in the number of cancer-fighting T cells in the tumor. Immune checkpoint blockade can then be used to ensure that these T cells remain activated, enhancing their ability to defeat cancer.

"Our findings provide a new molecular mechanism by which an ARID1A mutation may contribute to an anti-tumor immune response," says Hargreaves. "What's exciting about these findings is their translational potential. We can use ARID1A mutations to select patients for immune checkpoint blockade, and we now see a mechanism by which drugs that inhibit ARID1A or its protein complex could be used to further enhance immunotherapy in other patients."

By describing the mechanism by which immune checkpoint blockade is more effective in ARID1A-mutated cancers, the researchers provide clinicians with a rationale for prioritizing this immunotherapy for patients with an ARID1A mutation. These findings are an important step toward personalizing cancer treatment and inspire the development of new therapies that target ARID1A and its protein complex.

Going forward, the Salk Institute team hopes their findings will improve treatment outcomes for patients with various types of cancer associated with ARID1A mutations, and intends to explore this clinical translation in collaboration with the University of California, San Diego.