Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.

Autor:	Baldwin JG; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: jeremy.baldwin@ukr.de., Heuser-Loy C; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany., Saha T; Center for Engineered Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA., Schelker RC; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany., Slavkovic-Lukic D; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany., Strieder N; Next Generation Sequencing Core, Leibniz Institute for Immunotherapy, Regensburg, Germany., Hernandez-Lopez I; Next Generation Sequencing Core, Leibniz Institute for Immunotherapy, Regensburg, Germany., Rana N; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany; University of Regensburg, Regensburg, Germany., Barden M; Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany., Mastrogiovanni F; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany., Martín-Santos A; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany., Raimondi A; Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy., Brohawn P; Translational Science and Experimental Medicine, Early R&I, AstraZeneca, Gaithersburg, MD, USA., Higgs BW; Genmab, Princeton, NJ, USA., Gebhard C; Next Generation Sequencing Core, Leibniz Institute for Immunotherapy, Regensburg, Germany., Kapoor V; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Telford WG; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Gautam S; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Xydia M; Bavarian Cancer Research Center (BZKF), Regensburg, Germany; Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany., Beckhove P; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany; University of Regensburg, Regensburg, Germany; Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany., Frischholz S; Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany., Schober K; Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; FAU Profile Center Immunomedicine, FAU Erlangen-Nürnberg, Erlangen, Germany., Kontarakis Z; Genome Engineering and Measurement Laboratory (GEML), ETH Zürich, Zürich, Switzerland; Functional Genomics Center Zürich, ETH Zürich, University of Zürich, Zürich 8057, Switzerland., Corn JE; Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland., Iannacone M; Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Inverso D; Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Rehli M; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany; Next Generation Sequencing Core, Leibniz Institute for Immunotherapy, Regensburg, Germany., Fioravanti J; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Sengupta S; Center for Engineered Therapeutics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA. Electronic address: shiladit@mit.edu., Gattinoni L; Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; University of Regensburg, Regensburg, Germany; Center for Immunomedicine in Transplantation and Oncology, University Hospital Regensburg, Regensburg, Germany. Electronic address: luca.gattinoni@lit.eu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Sep 12. Date of Electronic Publication: 2024 Sep 12.
DOI:	10.1016/j.cell.2024.08.029
Abstrakt:	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. Competing Interests: Declaration of interests J.G.B., T.S., J.F., S.S., and L.G. have a patent application for the use of mitochondrial transfer technology in cancer immunotherapies. P.B. and S.G. have an employee relationship and have stock in AstraZeneca. B.W.H. has an employee relationship and has stock in Genmab. L.G. has consulting agreements with Lyell Immunopharma, Instil Bio, and Advaxis. L.G. is on the scientific advisory board of Poseida Therapeutics and Kiromic and a stockholder of Poseida Therapeutics. M.I. participates in advisory boards/consultancies for Gilead Sciences, Third Rock Ventures, Antios Therapeutics, Asher Biotherapeutics, GentiBio, Clexio Biosciences, Sybilla, and BlueJay Therapeutics. J.F. has an employee relationship and has stock in Lyell Immunopharma. S.S. is a founder and owns equity in Vyome Therapeutics Inc. and Alyssum Therapeutics Inc. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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