Mechanism of Lung Cancer Metastasis Identified

Inhibiting immune cells’ oxygen-sensing capability prevented lung metastasis in mice.

Oxygen-sensing proteins within T cells promote tumor growth in the lungs of mice, a recent study published in Cell found.

Prior research indicates these proteins limit inflammation in the lungs. However, findings from the new study showed that oxygen also suppresses the anticancer activity of T cells, allowing cancer cells that metastasized to the lungs to escape an attack from the immune system, and set up metastatic colonies.

“Since the lung is one of the most frequent sites to which cancers spread, we hypothesized that there might be unique immunologic processes that aid tumor cells in their ability to establish themselves in the lung,” said researcher David Clever, MD, PhD. “Because oxygen is a pervasive local environmental factor in the lung, we wanted to examine what role oxygen might play in regulating immunity in the lung.”

These oxygen-sensing proteins called prolyl hydroxylase domain (PHD) proteins, were found to act within T cells to prevent overly strong immune responses to particles that frequently enter the lung and cause no harm. PHD proteins promote regulatory T cell development, and limit the development of inflammatory T cells, restraining their ability to produce molecules involved in killing cancer.

In order to test whether or not PHD proteins promoted tumor cell growth in the lungs, researchers used a knockout mouse strain that lacked PHD proteins in its T cells. Melanoma cells were then injected into the knockout mice and unaltered normal mice.

The results of the study showed that in normal unaltered mice, there were large quantities of cancerous melanoma cells in the lungs, while the PHD-knockout mice showed almost no evidence of melanoma in the lungs.

The findings prompted researchers to examine whether or not inhibiting PHD proteins could improve the efficacy of adoptive cell transfer. To perform this experiment, researchers expanded the antitumor T cells in the presence of dimethyloxaloylglycine (DMOG), a drug designed to block PHD activity.

Researchers found that in the lab, the drug treatment improved the cancer-killing properties of the T cells. When the treatment was given to mice with established metastatic cancer, there was a significant improvement in the ability of drug-treated T cells to eliminate cancer compared with the untreated T cells.

The authors noted that in other studies, treatment with DMOG has been found to improve the cancer-killing properties of human T cells. The application of the study’s findings to human adoptive cell transfer immunotherapy clinical trials is currently being investigated by the researcher team.

“Adoptive cell transfer immunotherapy provides a unique opportunity for manipulation of a patient’s own T cells out of the body,” said researcher Nicholas Restifo, MD. “Although our finding is in mice, we are eager to test whether disruption of the oxygen-sensing machinery in T cells — with drugs, genetics, or regulation of environmental oxygen – will enhance the efficacy of T cell mediated immune therapies for cancer in humans.”