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

Baldwin JG, Heuser-Loy C, Saha T, Schelker R, Slavkovic-Lukic D, Strieder N, Hernandez-Lopez I, Rana N, Barden M, Mastrogiovanni F, Martín-Santos A, Raimondi A, Brohawn P, Higgs BW, Gebhard C, Kapoor V, Telford WG, Gautam S, Xydia M, Beckhove P, Frischholz S, Schober K, Kontarakis Z, Corn JE, Iannacone M, Inverso D, Rehli M, Fioravanti J, Sengupta S, Gattinoni L (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Cell Elsevier

DOI: 10.1016/j.cell.2024.08.029

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.

Authors with CRIS profile

Sina Frischholz Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Kilian Schober Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich CH Switzerland (CH) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) IT Italy (IT) Universitätsklinikum Regensburg DE Germany (DE) Leibniz-Institut für Immuntherapie (LIT) / Leibniz Institute for Immunotherapy DE Germany (DE) Harvard University US United States (USA) (US) AstraZeneca UK Limited GB United Kingdom (GB) Genmab US, Inc. US United States (USA) (US) National Cancer Institute (NCI) US United States (USA) (US)

How to cite

APA:

Baldwin, J.G., Heuser-Loy, C., Saha, T., Schelker, R., Slavkovic-Lukic, D., Strieder, N.,... Gattinoni, L. (2024). Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell. https://doi.org/10.1016/j.cell.2024.08.029

MLA:

Baldwin, Jeremy G., et al. "Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy." Cell (2024).

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