Q1 · CROSS-FIELD
ArticleOA
Author: Muhammad, Khalid ; Klein, Matthias ; Romero, Rossana ; Bauer, Christian A ; Riester, Zeno ; Mulder, Imke E ; Raifer, Hartmann ; Nerreter, Thomas ; Lauth, Matthias ; Wempe, Anne ; Picard, Felix ; Fischer, Florence ; Baldrich, Adrian ; Visekruna, Alexander ; Ohl, Kim ; Reichardt, Nicole ; Steinhoff, Ulrich ; Leister, Hanna ; Bopp, Tobias ; Luu, Maik ; Danhof, Sophia ; Huber, Magdalena ; Hudecek, Michael ; Busetti, Alessandro ; Yuille, Samantha ; Gress, Thomas M
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.