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. enrico.lugli@humanitasresearch.it.
# 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.

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