TY - JOUR
T1 - Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer
AU - Luu, Maik
AU - Riester, Zeno
AU - Baldrich, Adrian
AU - Reichardt, Nicole
AU - Yuille, Samantha
AU - Busetti, Alessandro
AU - Klein, Matthias
AU - Wempe, Anne
AU - Leister, Hanna
AU - Raifer, Hartmann
AU - Picard, Felix
AU - Muhammad, Khalid
AU - Ohl, Kim
AU - Romero, Rossana
AU - Fischer, Florence
AU - Bauer, Christian A.
AU - Huber, Magdalena
AU - Gress, Thomas M.
AU - Lauth, Matthias
AU - Danhof, Sophia
AU - Bopp, Tobias
AU - Nerreter, Thomas
AU - Mulder, Imke E.
AU - Steinhoff, Ulrich
AU - Hudecek, Michael
AU - Visekruna, Alexander
N1 - Funding Information:
We would like to thank Anne Hellhund for excellent technical support and research group A. Beilhack for providing us with OT-I mice. The technical expertise in breeding and maintaining of SPF and GF animals by staff of animal facility, Biomedical Research Center, Philipps-University of Marburg, is gratefully acknowledged. We also thank Suchita Panda, Christoph Mörtelmaier, and Iain Robertson from 4D Pharma Research Ltd. for their technical support. We are grateful to Michael Lohoff (Philipps-University of Marburg), Julia Benzel (DKFZ Heidelberg), Felix Schneider (Philipps-University of Marburg), Wolfgang Bywalez and Andrew Kaiser (Miltenyi Biotec GmbH) for helpful discussions. This project is supported by the Von Behring-Röntgen-Stiftung (Maik Luu and Ulrich Steinhoff), Stiftung PE Kempkes (Maik Luu), German Cancer Aid (Deutsche Krebshilfe e. V., Max Eder Program, grant no. 70110313 to Michael Hudecek), FAZIT-Stiftung (Hanna Leister and Alexander Visekruna) and the German Research Foundation (grants DFG-KFO325 to Thomas M Gress, Matthias Lauth, Christian A Bauer, Felix Picard, Magdalena Huber and Alexander Visekruna, DFG SFB1292 TP01 to Tobias Bopp, as well as DFG SFB/TRR 221, project no. 324392634 to Michael Hudecek).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-24331-1
DO - 10.1038/s41467-021-24331-1
M3 - Article
C2 - 34210970
AN - SCOPUS:85109186277
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4077
ER -