Researchers from the Johns Hopkins Kimmel Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy, and Johns Hopkins Bloomberg School of Public Health announced on March 31 that they have identified how the nutrient cysteine influences key functions of CD8+ T cells. The findings were published in Cell.
The research shows that cysteine is needed by T cells for two competing processes: helping the immune cells multiply and enabling them to kill cancer cells. Inside T cells, cysteine is divided between pathways that support cell growth and those that regulate immune activity. One pathway uses cysteine to produce glutathione, an antioxidant involved in controlling immune function, while another supplies sulfur for iron-sulfur clusters with help from the enzyme NFS1.
Laboratory and animal model experiments revealed that when cysteine was limited, T cells became more active against cancer but lost their ability to multiply. Disrupting iron-sulfur cluster formation weakened anti-tumor immunity by reducing T-cell expansion. In mouse models of melanoma skin cancer, T cells without NFS1 had reduced tumor control and showed signs of exhaustion. Increasing NFS1 activity improved both proliferation and tumor control.
Beth Kelly, Ph.D., first author and research associate in the Pearce laboratory, said these results suggest it may be possible to selectively change how cysteine is used inside a T cell: "The goal... would be to preserve beneficial function and prevent CD8+ T-cell exhaustion." Pearce added: "Understanding how these pathways work gives us new opportunities to fine-tune T-cell responses in cancer and other diseases."
The study was supported by several organizations including the Van Andel Institute Metabolism & Nutrition Program, Canadian Institutes of Health Research Fellowship, Paul G. Allen Frontiers Group Distinguished Investigator Program, Chan Zuckerberg Initiative (CZI), National Institute of Allergy and Infectious Diseases grants R01AI165722 and R01AI156274, as well as a Bloomberg Distinguished Professorship.
Pearce disclosed serving as a scientific advisory board member for Cour Pharma, Remedy Plan, and ImmunoMet Therapeutics.
