Researchers reveal how cancer shuts down T cells

ANN ARBOR, Michigan—If cancer is a series of puzzles, a new study has pieced together how several of those puzzles connect to form a bigger picture. One major piece is the immune system and why T cells stop doing their job. Another piece involves how histones are altered within immune cells, and a third piece is how a cell’s metabolism processes amino acids.

“Nobody knew if those questions were all connected. We were able to place several of these puzzles together and see how it works,” said Weiping Zou, M.D., Ph.D., Charles B. de Nancrede Professor of Surgery, Immunology and Biology at the University of Michigan and director of the Center of Excellence for Immunology and Immunotherapy at the U-M Rogel Cancer Center.

Zou is senior author on the paper, which was published in Nature. Multiple labs from the Rogel Cancer Center and collaborators from Poland were also involved in the study, which found a connection between these three separate puzzles. The study suggests that targeting the amino acid methionine transporter in tumor cells could make immunotherapy effective against more types of cancer.

The picture begins with T cells. Cancer can prevent T cells from mounting an attack against it. But what causes this?

Researchers looked at the tumor microenvironment, into how tumors metabolize amino acids. They found that an amino acid called methionine had the most impact on T cell survival and function. T cells with low levels of methionine became abnormal. Low methionine in the T cells also altered histone patterns that caused T cells to be impaired.

Introducing tumor cells to the picture creates a fight between the tumor cells and the T cells for methionine. Over and over, the tumor cells win the fight — taking the methionine from the T cells and rendering them ineffective. Previous research has considered a systemic approach to starve tumor cells of methionine, with the idea that the tumor cells are addicted to it. But, Zou noted, this study shows why that approach may be a double-edged sword.

“You have competition between tumor cells and T cells for methionine. The T cells also need it. If you starve the tumor cells of methionine, the T cells don’t get it either,” Zou pointed out. “You want to selectively delete the methionine for the tumor cells and not for the T cells.”

The study also found that supplementing methionine actually restored T cell function. High enough levels of methionine meant there was enough for both tumor cells and T cells. Tumor cells have more of the transporters that deliver methionine, and researchers found that impairing those transporters resulted in healthier T cells, as the T cells could compete for methionine.

“There are still a lot of mechanistic details we have not worked out, particularly the detailed metabolic pathways of methionine metabolism,” continued Zou. “We also need to understand how metabolism pathways may be different from tumor cells and T cells. We hope to find a target that is relatively specific to tumor cells so that we do not harm the T cells but impact the tumor.”

Zou has been awarded a $3.2 million grant from the National Cancer Institute to advance this work. He is also working with drug discovery experts to identify a small molecule inhibitor that targets methionine in tumor cells.