1. NaCl enhances CD8 + T cell effector functions in cancer immunotherapy.
- Author
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Scirgolea C, Sottile R, De Luca M, Susana A, Carnevale S, Puccio S, Ferrari V, Lise V, Contarini G, Scarpa A, Scamardella E, Feno S, Camisaschi C, De Simone G, Basso G, Giuliano D, Mazza EMC, Gattinoni L, Roychoudhuri R, Voulaz E, Di Mitri D, Simonelli M, Losurdo A, Pozzi D, Tsui C, Kallies A, Timo S, Martano G, Barberis E, Manfredi M, Rescigno M, Jaillon S, and Lugli E
- Subjects
- Animals, Mice, Humans, Cell Differentiation, Tumor Microenvironment immunology, Neoplasms immunology, Neoplasms therapy, Neoplasms drug therapy, Cell Line, Tumor, Interferon-gamma metabolism, Glutamine metabolism, Mice, Inbred C57BL, Immunotherapy, Adoptive methods, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Sodium Chloride, Immunotherapy methods
- Abstract
CD8
+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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