Immunmodulatorische Wirkung von bakteriellem Metabolit Pentanoat auf Lymphozyten
Zusammenfassung der Projektergebnisse
During the founding period, as applied, we focused on the impact of microbial metabolite pentanoate on the activity of T and B lymphocytes. Of particular interest was the identification of signaling pathways and epigenetic modifications that were involved in pentanoate-mediated regulation of the function and differentiation of various T and B cell subsets. In a close collaborative work with Yoav Shaul, we described a context-dependent function of the SCFA in shaping anti-inflammatory and anti-cancer immunity. We found that B cells stimulated with either CpG or LPS strongly enhanced their IL-10 production and anti-inflammatory capacity in the presence of pentanoate. Moreover, the characterization of pentanoate-treated T lymphocytes led to the conclusion that this SCFA changed their cytokine profile leading to increased expression of factors associated with cytotoxic activity. By elucidating the basis of penanote-mediated effects, we found that pentanoate is a strong inhibitor of class I HDAC enzymes. In the second part of this project, the influence of pentanoate on adoptive T cell therapy using antigen-specific CD8+ CTLs and CAR T cells was investigated in mouse models of pancreatic cancer and melanoma. Pentanoate was capable of triggering strong production of effector molecules in CTLs and CAR T cells, resulting in increased anti-tumor activity and improved therapeutic outcome in both experimental models of cancer. These data indicate that specific gut microbiota-derived metabolites such as the SCFA pentanoate have a strong potential to optimize immunotherapy for cancer in humans.
Projektbezogene Publikationen (Auswahl)
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The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nature Communications, 10(1).
Luu, Maik; Pautz, Sabine; Kohl, Vanessa; Singh, Rajeev; Romero, Rossana; Lucas, Sébastien; Hofmann, Jörg; Raifer, Hartmann; Vachharajani, Niyati; Carrascosa, Lucia Campos; Lamp, Boris; Nist, Andrea; Stiewe, Thorsten; Shaul, Yoav; Adhikary, Till; Zaiss, Mario M.; Lauth, Matthias; Steinhoff, Ulrich & Visekruna, Alexander
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Microbial metabolites: novel therapeutic tools for boosting cancer therapies. Trends in Cell Biology, 31(11), 873-875.
Luu, Maik & Visekruna, Alexander
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Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nature Communications, 12(1).
Luu, Maik; Riester, Zeno; Baldrich, Adrian; Reichardt, Nicole; Yuille, Samantha; Busetti, Alessandro; Klein, Matthias; Wempe, Anne; Leister, Hanna; Raifer, Hartmann; Picard, Felix; Muhammad, Khalid; Ohl, Kim; Romero, Rossana; Fischer, Florence; Bauer, Christian A.; Huber, Magdalena; Gress, Thomas M.; Lauth, Matthias ... & Visekruna, Alexander
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The Role of Short-Chain Fatty Acids and Bile Acids in Intestinal and Liver Function, Inflammation, and Carcinogenesis. Frontiers in Cell and Developmental Biology, 9.
Visekruna, Alexander & Luu, Maik
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Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells. Mucosal Immunology, 18(1), 66-75.
Luu, Maik; Krause, Felix F.; Monning, Heide; Wempe, Anne; Leister, Hanna; Mainieri, Lisa; Staudt, Sarah; Ziegler-Martin, Kai; Mangold, Kira; Kappelhoff, Nora; Shaul, Yoav D.; Göttig, Stephan; Plaza-Sirvent, Carlos; Schulte, Leon N.; Bekeredjian-Ding, Isabelle; Schmitz, Ingo; Steinhoff, Ulrich & Visekruna, Alexander
