Scirgolea and Sottile et al. showed that CD8+ T cells use NaCl to promote potent T cell effector functions. NaCl supplementation induced effector differentiation, IFNγ production, and cytotoxicity while maintaining stem-like plasticity. NaCl-mediated reprogramming depended on increased glutamine consumption from the microenvironment, leading to transcriptional, metabolic, and epigenetic remodeling, recapitulating PD-1 blockade-mediated T cell reinvigoration. A short pulse with excess NaCl in vitro reprogramed MART-1-specific CD8+ T cell function to exert more potent effector functions and tumor control in NSG mice.
Contributed by Shishir Pant
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.
Author Info: (1) IRCCS Humanitas Research Hospital, Milan, Italy. (2) IRCCS Humanitas Research Hospital, Milan, Italy. (3) IRCCS Humanitas Research Hospital, Milan, Italy. (4) IRCCS Humanitas R
Author Info: (1) IRCCS Humanitas Research Hospital, Milan, Italy. (2) IRCCS Humanitas Research Hospital, Milan, Italy. (3) IRCCS Humanitas Research Hospital, Milan, Italy. (4) IRCCS Humanitas Research Hospital, Milan, Italy. (5) IRCCS Humanitas Research Hospital, Milan, Italy. (6) IRCCS Humanitas Research Hospital, Milan, Italy. Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Milan, Italy. (7) IRCCS Humanitas Research Hospital, Milan, Italy. (8) IRCCS Humanitas Research Hospital, Milan, Italy. (9) IRCCS Humanitas Research Hospital, Milan, Italy. (10) IRCCS Humanitas Research Hospital, Milan, Italy. (11) IRCCS Humanitas Research Hospital, Milan, Italy. (12) IRCCS Humanitas Research Hospital, Milan, Italy. (13) IRCCS Humanitas Research Hospital, Milan, Italy. (14) IRCCS Humanitas Research Hospital, Milan, Italy. (15) IRCCS Humanitas Research Hospital, Milan, Italy. (16) IRCCS Humanitas Research Hospital, Milan, Italy. (17) IRCCS Humanitas Research Hospital, Milan, Italy. (18) Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy (LIT), Regensburg, Germany. University of Regensburg, Regensburg, Germany. Center for Immunomedicine in Transplantation and Oncology (CITO), University Hospital Regensburg, Regensburg, Germany. (19) Department of Pathology, University of Cambridge, Cambridge, UK. Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK. (20) Department of Biomedical Sciences, Humanitas University, Milan, Italy. Division of Thoracic, IRCCS Humanitas Research Hospital, Milan, Italy. (21) IRCCS Humanitas Research Hospital, Milan, Italy. Department of Biomedical Sciences, Humanitas University, Milan, Italy. (22) IRCCS Humanitas Research Hospital, Milan, Italy. Department of Biomedical Sciences, Humanitas University, Milan, Italy. (23) IRCCS Humanitas Research Hospital, Milan, Italy. (24) IRCCS Humanitas Research Hospital, Milan, Italy. Department of Biomedical Sciences, Humanitas University, Milan, Italy. (25) The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia. (26) The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia. (27) IRCCS Humanitas Research Hospital, Milan, Italy. (28) IRCCS Humanitas Research Hospital, Milan, Italy. Institute of Neuroscience, National Research Council of Italy (CNR) c/o Humanitas Mirasole S.p.A, Milan, Italy. (29) Department of Sciences and Technological Innovation, University of Piemonte Orientale, Alessandria, Italy. (30) Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy. (31) IRCCS Humanitas Research Hospital, Milan, Italy. Department of Biomedical Sciences, Humanitas University, Milan, Italy. (32) IRCCS Humanitas Research Hospital, Milan, Italy. Department of Biomedical Sciences, Humanitas University, Milan, Italy. (33) IRCCS Humanitas Research Hospital, Milan, Italy. enrico.lugli@humanitasresearch.it.
