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1.
EMBO Rep ; 23(12): e54685, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36215678

RESUMO

Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed increased levels of genome-wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate-treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotypes into regulatory T cells.


Assuntos
Ácido Láctico , Células Th17 , Animais , Camundongos , Epigenômica
2.
Nat Commun ; 12(1): 4077, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210970

RESUMO

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.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fatores Imunológicos/metabolismo , Imunoterapia Adotiva/métodos , Microbiota/fisiologia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Butiratos/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Imunoterapia , Interferon gama , Subunidade alfa de Receptor de Interleucina-2 , Megasphaera , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Receptores Acoplados a Proteínas G/genética , Fator de Necrose Tumoral alfa
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