NaCl enhances CD8+ T cell effector functions in cancer immunotherapy

  • Nat Immunol. 2024 Oct;25(10):1845-1857. doi: 10.1038/s41590-024-01923-9.
Caterina Scirgolea  #  1 ,  Rosa Sottile  #  1 ,  Marco De Luca  1 ,  Alberto Susana  1 ,  Silvia Carnevale  1 ,  Simone Puccio  1  2 ,  Valentina Ferrari  1 ,  Veronica Lise  1 ,  Giorgia Contarini  1 ,  Alice Scarpa  1 ,  Eloise Scamardella  1 ,  Simona Feno  1 ,  Chiara Camisaschi  1 ,  Gabriele De Simone  1 ,  Gianluca Basso  1 ,  Desiree Giuliano  1 ,  Emilia Maria Cristina Mazza  1 ,  Luca Gattinoni  3  4  5 ,  Rahul Roychoudhuri  6  7 ,  Emanuele Voulaz  8  9 ,  Diletta Di Mitri  1  8 ,  Matteo Simonelli  1  8 ,  Agnese Losurdo  1 ,  Davide Pozzi  1  8 ,  Carlson Tsui  10 ,  Axel Kallies  10 ,  Sara Timo  1 ,  Giuseppe Martano  1  11 ,  Elettra Barberis  12 ,  Marcello Manfredi  13 ,  Maria Rescigno  1  8 ,  Sebastien Jaillon  1  8 ,  Enrico Lugli  14
Affiliations
  • 1. IRCCS Humanitas Research Hospital, Milan, Italy.
  • 2. Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Milan, Italy.
  • 3. Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy (LIT), Regensburg, Germany.
  • 4. University of Regensburg, Regensburg, Germany.
  • 5. Center for Immunomedicine in Transplantation and Oncology (CITO), University Hospital Regensburg, Regensburg, Germany.
  • 6. Department of Pathology, University of Cambridge, Cambridge, UK.
  • 7. Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK.
  • 8. Department of Biomedical Sciences, Humanitas University, Milan, Italy.
  • 9. Division of Thoracic, IRCCS Humanitas Research Hospital, Milan, Italy.
  • 10. The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
  • 11. Institute of Neuroscience, National Research Council of Italy (CNR) c/o Humanitas Mirasole S.p.A, Milan, Italy.
  • 12. Department of Sciences and Technological Innovation, University of Piemonte Orientale, Alessandria, Italy.
  • 13. Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
  • 14. IRCCS Humanitas Research Hospital, Milan, Italy. [email protected].
  • # Contributed equally.
PMID: 39198631 DOI: 10.1038/s41590-024-01923-9
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112683
    V-9302
    99.46%, ASCT2 Antagonist
    target: ASCT
    Research Areas: Cancer