The rare and aggressive form of liver cancer has long been resistant to immunotherapy, which helps the body’s own immune system attack cancer cells. Now, researchers have identified a potential way to overcome that resistance using an FDA-approved drug already available for another medical condition.
The findings suggest a potential new treatment strategy for fibrolamellar carcinoma, a rare liver cancer that primarily affects children and young adults.
Fibrolamellar carcinoma accounts for approximately 2% of all liver cancer cases. There is currently no cure, the disease is often discovered only after it has spread to other parts of the body, and many patients have limited treatment options and poor survival prospects.
How fibrolamellar carcinoma evades the immune system
Research published in journals Gastroenterologyreveals why immunotherapy is struggling against this cancer.
Researchers found that fibrolamellar tumors change their surrounding environment, preventing immune T cells from reaching the cancer. Instead of entering the tumor and attacking cancer cells, the T cells become trapped elsewhere. This process, known as T-cell exclusion, effectively blocks the immune system from performing its normal cancer-fighting role.
The researchers also found that AMD3100, a drug already approved by the U.S. Food and Drug Administration for another disease, can interfere with this process. This drug prevents tumors from capturing T cells, allowing immune cells to reach and attack the cancer.
“Our findings provide one of the first indications of why a type of immunotherapy called immune checkpoint blockade has not worked well in these patients, and tell us that even if this particular drug is not a panacea, this T-cell exclusion phenomenon is an important phenomenon to address in fibrolamellar carcinoma,” said Praveen Sethupathi ’03, chair of the Department of Biomedical Sciences and professor of physiology and genomics in the College of Veterinary Medicine. medicine.
Sethupathi served as co-senior author of the study, along with Dr. Venu Pillarisetti, a surgical oncologist at the University of Washington.
Elucidating the tumor environment using advanced technology
To better understand what’s going on inside these tumors, researchers used a powerful technique known as mononuclear transcriptomics.
This technique allowed the team to isolate the nuclei of individual cells within tumor tissue and determine which genes were active in each cell. This approach has provided an unprecedented perspective on the tumor microenvironment and the interactions occurring within it.
“It was only when we had access to this technology that we began to get a clear picture of the tumor microenvironment,” said study co-lead author Andreas Stefanou, a graduate student at Cornell University who was co-supervised by Setsupathy and Iwin de Vlaminck, associate professor at Duffield Polytechnic Institute’s Meinig School of Biomedical Engineering.
Why immunotherapy sometimes fails
Immune checkpoint inhibitors work by activating the body’s own T cells and encouraging them to migrate to tumors where they can destroy cancer cells.
These treatments have shown significant benefit in several cancers, including melanoma as well as liver, lung, kidney, and bladder cancers. However, many other cancers, such as pancreatic cancer, prostate cancer, and brain cancer, often do not respond well to these treatments.
Researchers say features of the tumor microenvironment, including T cell exclusion, may help explain why some cancers remain resistant to immune checkpoint inhibitors.
Role of fibrous bands in tumors
Fibrolamellar carcinoma gets its name from the thick bands of fibers that extend throughout the tumor.
“Despite recent advances in the study of this cancer, we have yet to pinpoint exactly how, if at all, these fibrous bands contribute to tumor progression,” Professor Stefanou said.
The researchers discovered that these bands are produced by stellate cells, which are normal liver cells that have been altered by cancer. As the stellate cells change, they release fibrillar proteins that build up the characteristic bands within the tumor.
Using single-cell technology, the research team discovered that these altered astrocytes also signaled nearby T cells. These signals guide immune cells away from cancer cells and toward the fibrous zone where T cells are trapped.
AMD3100 restores access to immune cells
“So we thought, what if we blocked this signaling in T cells with a compound?” Sethupathy said.
To test this idea, researchers in the Pillarisetti lab at the University of Washington used slices of tumor tissue from patients and treated them with AMD3100.
The results showed that the drug was successful in bringing T cells back to the center of the tumor. Combining AMD3100 with immune checkpoint inhibition further increased T cell activation and significantly increased tumor cell death.
The researchers are currently looking for liver cancer experts interested in starting a clinical trial to evaluate treatment approaches for patients.
“An attractive feature of this study is that AMD3100 is already FDA approved, which could reduce risks and shorten the timeline for clinical trials in fibrolamellar carcinoma,” Sethupathi said.
Co-first authors of the study were Jason Carter and Lindsey Dickerson, members of the Pillarisetti lab at the University of Washington. Bo Shui, a senior researcher in the Setsupathy lab, is also a co-author.
This research was supported by funding from the Fibrolamellar Cancer Foundation.
