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Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function

Ardena Berisha, Benjamin Jenkins, Nidhi Kedia-Mehta, Eimear K Ryan, Shauna Mayock, Odhran Ryan, Cian Davis, Helen Heneghan, Donal O’Shea, Nick Jones Orcid Logo, Andrew E Hogan

The Journal of Immunology, Volume: 215, Issue: 4, Start page: vkag073

Swansea University Authors: Benjamin Jenkins, Nick Jones Orcid Logo

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DOI (Published version): 10.1093/jimmun/vkag073

Abstract

Mucosal-associated invariant T (MAIT) cells are unconventional T cells, which upon activation can display potent cytotoxic and cytokine-producing capabilities. Together, these features make MAIT cells promising candidates for cancer immunotherapy. In this study, we show that MAIT cells can be effici...

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Published in: The Journal of Immunology
ISSN: 0022-1767 1550-6606
Published: Oxford University Press (OUP) 2026
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa71892
Abstract: Mucosal-associated invariant T (MAIT) cells are unconventional T cells, which upon activation can display potent cytotoxic and cytokine-producing capabilities. Together, these features make MAIT cells promising candidates for cancer immunotherapy. In this study, we show that MAIT cells can be efficiently amplified in vitro, and these amplified MAIT cells are armed with potent anticancer functions, including the ability to produce significant amounts of effector molecules such as IFNγ and granzyme B. Excitingly, we demonstrate that MAIT cells can be redirected to potently kill cancerous cells using a clinically relevant bispecific monoclonal antibody. Furthermore, in an attempt to metabolically condition MAIT cells to improve function, we demonstrate that MAIT cells possess the molecular machinery to transport and metabolize lactate, an abundant metabolite within the solid tumor microenvironment. Activating MAIT cells in the presence of exogenous sodium lactate remodels their cellular metabolism, with a significant increase in mitochondrial metabolism. Functionally, this supports elevated production of effector molecules (IFNγ, granzymes A and B), leading to boosted engager mediated MAIT cell cytotoxicity. These data collectively show that MAIT cells can be pharmacologically directed to target cancer cells and in vitro conditioning using sodium lactate can enhance their anticancer capabilities through reprogrammed cellular metabolism. Our findings represent a novel strategy for a potential new adoptive cancer immunotherapy.
Keywords: BiTEs, immunotherapy, lactate, mucosal associated invariant T cells
College: Faculty of Medicine, Health and Life Sciences
Funders: This study is supported by the City of Dublin Skin and Cancer Hospital Charity. A.B. is supported by Maynooth University Hume Fellowship. Financial support for the Attune NxT was provided to Maynooth University Department of Biology by Science Foundation Ireland (16/RI/3399).
Issue: 4
Start Page: vkag073

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