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.
Highlights
Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules
Dominant commensal bacteria are not able to produce pentanoate. This short-chain fatty acids (SCFAs) is rather a rare bacterial metabolite generated by low-abundant commensals such as Megasphaera massiliensis, which we have classified as a pentanoate-producing bacterial species[21]. It has far been unknown if the ex vivo culture of cytotoxic T lymphocytes (CTLs) —either derived from the endogenous repertoire or through genetic engineering with a T cell receptor (TCR) or chimeric antigen receptor (CAR)—with bacterial metabolites is capable of augmenting their anti-tumor reactivity
When compared to 14 abundant bacterial species, which represent proportional distribution of the most common phyla in the human intestine (Firmicutes: Enterococcus faecalis, Faecalibacterium prausnitzii, Anaerostipes hadrus, Blautia coccoides, Dorea longicatena, Faecalicatena contorta and Ruminococcus gnavus; Bacteroidetes: Bacteroides fragilis, Parabacteroides distasonis, Bacteroides vulgatus, and Bacteroides ovatus; Actinobacteria: Bifidobacterium longum and Bifidobacterium breve; and Proteobacteria: Escherichia coli), we observed that the low-abundant human commensal M. massiliensis was the only bacterium synthesizing high amounts of pentanoate (Fig. 1a)
Summary
Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Previous studies have identified acetate, propionate, and butyrate as major microbial metabolites, belonging to the class of short-chain fatty acids (SCFAs) These were shown to promote the expansion of Tregs, but they seem to improve the function of effector T cells[10,11,12,13,14,15]. We demonstrate that the treatment with pentanoate and butyrate induces strong production of effector molecules in CTLs and CAR T cells, resulting in increased antitumor reactivity and improved therapeutic outcome. These data show that specific gut microbiota-derived metabolites such as butyrate and pentanoate have the potential to optimize adoptive T cell therapy for cancer in humans
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