Triple-negative breast cancer cells engage in a “glutamine steal” — outcompeting T cells for the nutrient glutamine and impairing their ability to kill tumor cells, Vanderbilt researchers have discovered.

The team found that an inhibitor of glutamine transport selectively targeted tumor cells and enhanced the antitumor immune response, suggesting it may be a promising therapeutic strategy for triple-negative breast cancer (TNBC). The studies were reported in the Journal of Clinical Investigation.

“Triple-negative” refers to the fact that TNBC cells do not have any of the three receptors — estrogen, progesterone and HER2 — blocked by targeted anticancer therapies. While such therapies have improved the survival of other types of breast cancer, TNBC prognosis remains grim, said Deanna Edwards, PhD, research instructor in Medicine and first author of the JCI paper.

“We’ve been trying to find other ways to target triple-negative breast cancer cells. We focused on glutamine metabolism because triple-negative cells are “addicted” to it; they require glutamine for survival and growth,” Edwards said.

The researchers genetically eliminated glutaminase, an enzyme required for the metabolism of glutamine, in TNBC cells and studied tumor growth in mouse models.

“When the tumor cells were not able to use glutamine, glutamine levels in the tumor increased, making glutamine available to other cells in the tumor microenvironment,” Edwards said.

They found that the increased glutamine levels improved antitumor T cell activation, which reduced tumor growth and metastasis.

The glutamine transporter inhibitor V-9302, developed at Vanderbilt by H. Charles Manning, PhD, and colleagues, also improved T cell activation and reduced tumor growth in the mouse models. The team found that V-9302 selectively blocked uptake of glutamine into the tumor cells, without affecting glutamine uptake by T cells.

“This was really surprising,” said Jin Chen, MD, PhD, professor of Medicine and Cell and Developmental Biology. “Not only did V-9302 not impact glutamine metabolism in T cells, but it actually made antitumor immunity better.”

T cells in the tumor microenvironment responded to the presence of V-9302 by increasing expression of a different glutamine transporter, the researchers showed. It is unclear why T cells were able to compensate for the inhibitor, but tumor cells were not.

“Using a drug like V-9302 is a way to selectively target glutamine consumption by tumor cells while sparing — and even improving the activity of — antitumor immune cells,” Edwards said.

V-9302 provides a promising lead, Chen said, for the development of small molecules that selectively block tumor uptake of glutamine and provide a two-pronged attack against TNBC: impairing tumor cell metabolic needs and boosting antitumor immune responses.

The concept of preventing the “glutamine steal” by tumor cells as a treatment strategy may be applicable beyond TNBC, Edwards noted. “Other types of tumors are also considered to be glutamine-addicted, so it’s possible that this phenomenon is playing out in other cancers as well.”

Other Vanderbilt investigators contributing to the research included Verra Ngwa, Ariel Raybuck, Shan Wang, Yoonha Hwang, Laura Kim, Sung Hoon Cho, Yeeun Paik, H. Charles Manning, Jeffrey Rathmell, Rebecca Cook, and Mark Boothby. The research was supported by the National Institutes of Health (grants CA177681, CA095004, CA250506, CA009592), U.S. Department of Veterans Affairs, and Susan G. Komen Foundation.

—Leigh MacMillan