Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy
Year: 2024
Type: article
Abstract: Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8 + T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8 + T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8 + T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.
Source: Cell
Authors: Jeremy G. Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C. Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W. Higgs, Claudia Gebhard, Veena Kapoor, William G. Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E. Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni
Institutions: National Institutes of Health, National Cancer Institute, Center for Cancer Research, Leibniz Institute for Immunotherapy, Brigham and Women's Hospital, Harvard University, Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, University Hospital Regensburg, University of Regensburg, IRCCS Ospedale San Raffaele, AstraZeneca (United States), Genmab (United States), Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, University of Zurich, ETH Zurich, Functional Genomics Center Zurich, Institute of Molecular Health Sciences, Vita-Salute San Raffaele University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: Fondazione AIRC per la ricerca sul cancro ETS, Cancer Research Institute, Gilead Sciences, Joachim Herz Stiftung, Vir Biotechnology, US-UK Fulbright Commission, European Commission, Fulbright Australia, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius-Stiftung, Ministero della Salute, Associazione Italiana per la Ricerca sul Cancro, Kinghorn Foundation, National Institutes of Health, European Research Council, Leibniz-Gemeinschaft, National Cancer Institute, H2020 European Research Council, H2020 Future and Emerging Technologies, HORIZON EUROPE European Innovation Council
Awards: G1010412108, G1358366600, G2020244936, G2076520454, G2191143425, G2205818929, CompLS -Runde 4 - Verbundprojekt: DeepTCR - Entwicklung von Fortgeschrittenen Deep-Learning-Ansätzen zur Analyse der T-Zell-Immunantwort auf Einzelzell-Ebene - Teilprojekt B, G3522017107, Multifunctional nanoparticles for targeting aberrant tumorigenic pathways, Functional Biology of Hepatic CD8+ T cells, G4298111437, G4433554031, G4457840320, G4472688592, AN IN VIVO BIOENGINEERED CHIP AS A SMART INTRAVITAL MULTIPHOTON IMAGING WINDOW FOR NEW VALIDATION PROTOCOLS OF BIOMATERIALS, GRK 2504: Neue antivirale Strategien: von der Chemotherapie bis zur Immunintervention, G6124110148, G6237202226, G650251704, G6646348494, G6814536618, AGEnTS - Genetisches Engineering von T-Zellen für die Therapie von Infektionserkrankungen, G7409471478, G7946718699, G7984971330, G8194005575, G8324994193, G8987646616, Combinatorial application of nanoscale technologies to target a novel mechanism of immune evasion by cancer cells, Tunneling Nanotube Inhibitors for Cancer Immunotherapy
OpenAlex ID: W4402515260