Lötscher et al. demonstrated the magnesium dependence of co-stimulatory cell-surface molecule LFA-1-mediated activation and effector function of CD8+ T cells. Upon interaction with extracellular magnesium, LFA-1 adopts its active conformation and initiates outside-in signaling on CD8+ T cells, leading to increases in calcium flux, metabolic reprogramming, immune synapse formation, and cytotoxicity. LFA-1-sensed magnesium sufficiency improved infection/tumor-specific T cell function and enhanced the effectiveness of immunotherapeutic modalities. In patients treated with CAR T cells and ICI, low serum magnesium levels correlated with poor prognosis.
Contributed by Shishir Pant
ABSTRACT: The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8(+) T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.
Author Info: (1) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (2) Department of Biomedicine, Immunobiology, Universit
Author Info: (1) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (2) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. (3) Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (4) Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland. (5) Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland. (6) Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (7) University of Applied Science Northwestern Switzerland, Institute for Ecopreneurship, 4132 Muttenz, Switzerland. (8) Division of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, 4031 Basel, Switzerland; Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland. (9) Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland. (11) Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland. (12) Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland. (13) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (14) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (15) Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland. (16) Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland. (17) Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (18) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. (19) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (20) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (21) Hornet Therapeutics Ltd, London SW1Y 5ES, UK; Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06510, USA. (22) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland. (23) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. (24) Swiss Group for Clinical Cancer Research, 3008 Bern, Switzerland; Department of Oncology, Cantonal Hospital Winterthur, 8400 Winterthur, Switzerland. (25) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department for Biomedical Research (DBMR), University Clinic for Diabetes, Endocrinology, Clinical Nutrition and Metabolism, Inselspital, University of Bern, 3008 Bern, Switzerland; Diabetes Center Berne (DCB), 3010 Bern, Switzerland. (26) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. (27) Department of Pharmaceutical Sciences, Pharmaceutical Technology, University of Basel, 4056 Basel, Switzerland. (28) Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland. (29) Department of Biomedicine, Immune Cell Biology, University and University Hospital of Basel, 4031 Basel, Switzerland. (30) Department of Biomedicine, Cancer Immunology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Division of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, 4031 Basel, Switzerland. (31) Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. Electronic address: chess@uhbs.ch.
