Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer

Maik Luu, Zeno Riester, Adrian Baldrich, Nicole Reichardt, Samantha Yuille, Alessandro Busetti, Matthias Klein, Anne Wempe, Hanna Leister, Hartmann Raifer, Felix Picard, Khalid Muhammad, Kim Ohl, Rossana Romero, Florence Fischer, Christian A. Bauer, Magdalena Huber, Thomas M. Gress, Matthias Lauth, Sophia Danhof, Tobias Bopp, Thomas Nerreter, Imke E. Mulder, Ulrich Steinhoff, Michael Hudecek () and Alexander Visekruna ()
Additional contact information
Maik Luu: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Zeno Riester: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
Adrian Baldrich: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
Nicole Reichardt: 4DPharma Research Ltd.
Samantha Yuille: 4DPharma Research Ltd.
Alessandro Busetti: 4DPharma Research Ltd.
Matthias Klein: Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz
Anne Wempe: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Hanna Leister: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Hartmann Raifer: Philipps University Marburg
Felix Picard: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Khalid Muhammad: United Arab Emirates University
Kim Ohl: RWTH Aachen University
Rossana Romero: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Florence Fischer: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Christian A. Bauer: University Hospital Marburg, UKGM, Philipps University Marburg
Magdalena Huber: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Thomas M. Gress: University Hospital Marburg, UKGM, Philipps University Marburg
Matthias Lauth: Institute of Molecular Biology and Tumor Research, Center for Tumor- and Immunobiology, Philipps-University Marburg
Sophia Danhof: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
Tobias Bopp: Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz
Thomas Nerreter: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
Imke E. Mulder: 4DPharma Research Ltd.
Ulrich Steinhoff: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg
Michael Hudecek: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
Alexander Visekruna: Institute for Medical Microbiology and Hygiene, Philipps-University Marburg

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.

Date: 2021
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DOI: 10.1038/s41467-021-24331-1

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