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.

Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy / Baldwin, J. G.; Heuser-Loy, C.; Saha, T.; Schelker, R.; Slavkovic-Lukic, D.; Strieder, N.; Hernandez-Lopez, I.; Rana, N.; Barden, M.; Mastrogiovanni, F.; Martin-Santos, A.; Raimondi, A.; Brohawn, P.; Higgs, B. W.; Gebhard, C.; Kapoor, V.; Telford, W. G.; Gautam, S.; Xydia, M.; Beckhove, P.; Frischholz, S.; Schober, K.; Kontarakis, Z.; Corn, J. E.; Iannacone, M.; Inverso, D.; Rehli, M.; Fioravanti, J.; Sengupta, S.; Gattinoni, L.. - In: CELL. - ISSN 0092-8674. - 187:23(2024), pp. 6614-6630.e21. [10.1016/j.cell.2024.08.029]

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

Iannacone M.
Membro del Collaboration Group
;
Inverso D.
Membro del Collaboration Group
;
2024-01-01

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.
2024
bone marrow stromal cells
cancer immunotherapy
CAR T therapy
CD8
+
T cells
immune metabolism
mitochondrial transfer
nanotubes
Talin 2
TCR-T therapy
TIL therapy
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/175236
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