A rare and aggressive form of liver cancer has long resisted immunotherapy, a treatment that 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 possible 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 and the disease is often discovered only after it has spread to other parts of the body, leaving many patients with limited treatment options and poor prospects for survival.
How fibrolamellar carcinoma evades the immune system
The study, published in the journal Gastroenterologysheds light on why immunotherapy has fought this cancer.
Researchers discovered that fibrolamellar tumors alter the environment around them in a way that prevents immune T cells from reaching the cancer. Instead of entering the tumor and attacking the cancer cells, the T cells become trapped elsewhere. This process, known as T cell exclusion, effectively prevents the immune system from carrying out its normal cancer-fighting function.
The team also found that AMD3100, a drug already approved by the US Food and Drug Administration for another disorder, can disrupt this process. By preventing tumors from trapping T cells, the drug allows those immune cells to reach and attack the cancer.
“Our results provide one of the first clues as to why a type of immunotherapy called immune checkpoint inhibition has not worked well in these patients, and even if this particular drug is not the end-all, be-all, it teaches us that it is important to address this T-cell exclusion phenomenon in fibrolamellar carcinoma,” said Praveen Sethupathy ’03, professor of physiological genomics and chair of the Department of Biomedical Sciences in the College of Veterinary Medicine.
Sethupathy was co-senior author of the study along with Dr. Venu Pillarisetty, a surgical oncologist at the University of Washington.
Advanced technology reveals tumor environment
To better understand what was happening inside these tumors, the researchers used a powerful technique known as single-nucleus transcriptomics.
This technology allowed the team to isolate the nuclei of individual cells within the tumor tissue and determine which genes were active in each cell. The approach provided unprecedented insight into the tumor microenvironment and the interactions taking place within it.
“It wasn’t until we were able to use this technology that the picture of the tumor microenvironment began to become clearer for us,” said Andreas Stephanou, a co-author of the study and a Cornell graduate student co-tutored by Sethupathy and Iwijn de Vlaminck, an associate professor in the Duffield College of Engineering’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 move toward tumors, where they can destroy cancer cells.
These therapies have produced significant benefits in several types of cancer, including liver, lung, kidney, and bladder cancers, as well as melanoma. However, many other cancers, including pancreatic, prostate, and brain cancers, often do not respond well to these treatments.
The researchers say that features of the tumor microenvironment, including T cell exclusion, may help explain why some cancers remain resistant to immune checkpoint inhibitors.
The role of fibrous bands in tumors
Fibrolamellar carcinoma gets its name from the thick fibrous bands that run through the tumors.
“Despite all the recent advances in the study of this cancer, we have not yet determined how these fibrous bands contribute, if at all, to tumor progression,” Stephanou said.
The researchers discovered that these bands are produced by stellate cells, which are normal liver cells that are altered by cancer. Once modified, the stellate cells release fibrous proteins that form the characteristic bands within the tumor.
Using single-cell technology, the team discovered that these altered stellate cells also send signals to nearby T cells. These signals direct the immune cells away from the cancer cells and toward the fibrous bands, where the T cells become trapped.
AMD3100 restores access to immune cells
“So we asked, what would happen if we blocked this signaling in T cells with a compound?” Sethupathy said.
To test that idea, researchers at the University of Washington’s Pillarisetty lab used slices of the patient’s tumor tissue and treated them with AMD3100.
The results showed that the drug successfully guided T cells back to the center of the tumors. When AMD3100 was combined with immune checkpoint inhibition, T cell activation was further increased, resulting in a significant increase in tumor cell death.
Researchers are now looking for liver cancer specialists interested in starting clinical trials to evaluate the treatment approach in patients.
“A compelling feature of this work is that AMD3100 is already approved by the FDA, which can reduce risks and potentially accelerate timelines for clinical trials in fibrolamellar carcinoma,” Sethupathy said.
The first authors of the study were Jason Carter and Lindsey Dickerson, both members of the Pillarisetty laboratory at the University of Washington. Bo Shui, senior research associate in the Sethupathy laboratory, was also a co-author.
The research was supported by funds from the Fibrolamellar Cancer Foundation.