Fibrolamellar carcinoma accounts for about 2% of liver cancer cases. It mostly strikes children and young adults, it has no cure, and doctors often find it only after it has spread. Immunotherapy has done little against it. A team led by Cornell University and the University of Washington now says it knows why, and has found an FDA-approved drug that reversed the problem in tumor samples.
The study appeared in the journal Gastroenterology. Its central finding is that the tumors reshape their surroundings so that immune T cells never reach the cancer. The cells get trapped elsewhere instead. The researchers call the effect T-cell exclusion.
“Our results provide among the first indications of why a type of immunotherapy called immune checkpoint inhibition hasn’t worked well in these patients,” said Praveen Sethupathy, a Cornell professor of physiological genomics and co-senior author. “Even if this particular drug isn’t the end-all-be-all, it teaches us that this T-cell exclusion phenomenon is an important one to tackle.”
Inside the tumor
The cancer takes its name from the thick fibrous bands that run through it. Nobody had pinned down what those bands do. “We still haven’t pinpointed how these fibrous bands contribute, if at all, to the tumor’s progression,” said Andreas Stephanou, a Cornell graduate student and co-first author.
The team used single-nucleus transcriptomics, which isolates the nucleus of individual cells and reads which genes are active in each. That work showed the bands are built by stellate cells, normal liver cells that the cancer alters. The changed cells release fibrous proteins. They also send signals that pull T cells toward the bands and away from the cancer cells.
“It wasn’t until we were able to use this technology that the picture of the tumor microenvironment began to clear up for us,” Stephanou said.
An existing drug
“So, then we asked, what if we were to block this signaling in T cells with a compound?” Sethupathy said. Researchers in the laboratory of Dr. Venu Pillarisetty, a surgical oncologist at the University of Washington and the study’s other co-senior author, treated slices of patient tumor tissue with AMD3100, a drug the FDA has already approved for another disorder.
It worked. T cells moved back into the center of the tumors. Adding an immune checkpoint inhibitor raised T-cell activation further and produced a significant rise in tumor cell death.
The experiments used tissue samples, not living patients. The team is looking for liver cancer specialists willing to run clinical trials. Sethupathy said the drug’s approval status “can reduce risks and potentially speed up timelines” for those trials.
The Fibrolamellar Cancer Foundation funded the research.
