A research team from the Johns Hopkins Kimmel Cancer Center, its Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Bloomberg School of Public Health have discovered how the immune system's CD8+ T cells use the nutrient cysteine to control two essential functions that compete for this resource — the immune cell's ability to multiply and its ability to kill cancer cells.
The study, published March 31 in Cell, shows that cysteine — an amino acid and fundamental building block for life — is required by T cells but is used in different ways. Once inside the cell, cysteine supply is split between two internal pathways that drive distinct T-cell behaviors. One pathway supports cell growth and proliferation, while the other regulates immune activity, including the production of cancer-fighting molecules.
Using a variety of laboratory and animal models, the team found that cysteine fuels the production of the antioxidant glutathione to regulate T-cell activity, but it also helps T cells multiply and sustain their cancer-fighting function by supplying sulfur for iron-sulfur (FeS) clusters, formed with the help of the enzyme NFS1.
"Once cysteine enters the cell, it can take on different fates," says senior author Erika Pearce, Ph.D., Bloomberg Distinguished Professor in the Department of Oncology and the Department of Biochemistry and Molecular Biology. "Understanding where it goes, and when, turns out to be essential for determining how T cells behave."
When the researchers limited cysteine in laboratory models, T cells became more active and produced higher levels of immune-signaling molecules that enhanced their cancer-killing function, but they also lost their ability to divide and multiply. Disrupting FeS cluster formation impaired T-cell expansion and weakened anti-tumor immunity.
Since cysteine works through various cell pathways to support different immune functions, Beth Kelly, Ph.D., first author and research associate in the Pearce laboratory, says the study points to the possibility for selectively modulating how cysteine is used inside a T cell, boosting it in certain pathways while inhibiting it in others. The goal, she says, would be to preserve beneficial function and prevent CD8+ T-cell exhaustion.
In laboratory studies of mouse models of melanoma skin cancer, the researchers found that T cells lacking NFS1 showed reduced tumor control and signs of exhaustion. In contrast, boosting NFS1 activity enhanced T-cell proliferation and improved tumor control. Blocking glutathione production after initial T-cell activation also strengthened anti-tumor responses.
The findings reveal a previously unrecognized level of metabolic control over immune cell function, the researchers say. Although more research is needed, the findings point to the potential to selectively direct how T cells use cysteine to support cancer-fighting immune responses and limit processes that suppress this activity.
"Understanding how these pathways work gives us new opportunities to fine-tune T-cell responses in cancer and other diseases," says Pearce.
In addition to Pearce and Kelly, other researchers participating in the study were Minsun Cha, Tatjana Gremelspacher, Jacob Martin, Massimo Andreis, Isha Maloo, Gustavo Carrizo, Mia Gidley, Michal Stanczak, Petya Apostolova, Joseph Longo, Lisa DeCamp, Eric Ma, Ryan Sheldon, Russell Jones, David Sanin and Ananya Majumdar.
The research was supported by the Van Andel Institute Metabolism & Nutrition (MeNu) Program (RRID: SCR_027494), Pathway-to-Independence Award and Canadian Institutes of Health Research (CIHR) Fellowship (MFE-181903), the Paul G. Allen Frontiers Group Distinguished Investigator Program, the Chan Zuckerberg Initiative (CZI), the National Institute of Allergy and Infectious Diseases (R01AI165722 and R01AI156274), and the Bloomberg Distinguished Professorship.
