Detection trick allows cancer to hide

In a surprising discovery, researchers found that cells from some cancers escaped destruction by the immune system by hiding inside other cancer cells.

The discovery, they hinted at in a paper published last month in the journal eLife, may explain why some cancers are able to resist treatments that are supposed to destroy them.

The research began when Yaron Carmi, an assistant professor at Tel Aviv University in Israel, was studying which immune system T cells might be the most potent in killing cancers. He started with lab experiments that looked at treatment-resistant melanoma and breast cancer in mice, studying why an attack by T cells that were engineered to destroy these tumors didn’t kill them.

He was looking at checkpoint inhibitors, a specific type of cancer therapy that involves removing proteins that normally stop T cells from attacking tumors. They are used to treat many types of cancer, including melanoma, colon and lung cancer. But sometimes, after a tumor appears to have been defeated by T cells, it recovers.

Carmi, who loves to look at cells under a microscope, began spying on tumors as T cells attacked them.

“I wanted to see the murder, the real murder,” he said.

Each time, however, he saw a few giant cells that remained after the T cells had done their work.

“I wasn’t sure what it was, so I thought I’d take a closer look,” he said.

The giant cells turned out to be cancers that harbored other cancer cells, protecting them from destruction. Once these escaped to their hiding places, the T cells could not reach them, even though the immune system killed the cancer cells that served as “bunkers”.

“It was like seeing the devil,” Carmi said.

Cancer cells, he added, can remain hidden “for weeks or months.”

When he removed the T cells from the Petri dishes, the cancer cells came out of their shelters.

He looked at human breast cancer, colon cancer and melanoma cells and saw the same phenomenon. But blood cancers and glioblastomas, the deadly brain cancers, did not form cell-within-cell structures.

Perhaps, reasoned Carmi, it is possible to prevent cancer cells from taking refuge. He decided to examine the genes involved in this defense mechanism. Blocking these genes, he found, also blocked the ability of T cells to attack tumors.

“I realized that this is the limit of what the immune system can do,” Carmi said. “Our immune system cannot win.”

Others, while fascinated by the discovery, say many questions remain.

“It’s definitely an interesting paper, with some strong and compelling observations,” said Dr. Michel Sadelain, an immunologist at the Memorial Sloan Kettering Cancer Center, where he directs the gene transfer and expression laboratory. But, he asked, how relevant is this finding to immunotherapies in the real world?

Dr. Marcela Maus, director of the cellular immunotherapy program at the Mass General Cancer Center, said the discovery shows what a new defense mechanism for cancer cells may be.

“We’ve seen that tumors can hide from the immune system, including a species that ‘pretends’ to be immune cells, but I don’t think we’ve ever seen tumor cells hide inside others.” “I think it needs to be replicated to gain full strength,” he added.

Dr. Jedd Wolchok, director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, had the same reaction.

“I’ve heard of cancer cells feeding on themselves, feeding on their neighbors, releasing exosomes,” he said, referring to tiny pockets of signaling chemicals. “I think that’s the next step: hiding inside the neighbor.”

One possible remedy, he said, might be to thwart the cancer cells by treating the patient with immunotherapy for a short period of time, then stopping and treating again. This may be in line with new questions about how long patients should be treated with these expensive and toxic drugs. The current recommendation is to treat for two years. But, Wolchok said, “but many of us ask ourselves, ‘Can you get away with less?'”

He cautioned, however, that the immunotherapy used by the Tel Aviv group was not standard in cancer patients.

For now, Wolchok said, while the finding is “a really groundbreaking observation,” it remains to be seen whether it will lead to improvements in the treatment of cancer patients.

Originally translated from English by Luiz Roberto M. Gonçalves