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

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 reprogramming. 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 on 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.

Maik Luu, Zeno Riester, Adrian Baldrich, Nicole Reichardt, Samantha Yuille, Alessandro Busetti, Matthias Klein, Anne Wempel, 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, Alexander Vise Kruna