evaluating-multimodal-functionality-chimeric-antigen-receptor-t-cells

Evaluating Multimodal Functionality of Chimeric Antigen Receptor T Cells at Single-Cell Resolution through Optofluidics Analysis

Adoptive T-cell therapy is a novel treatment paradigm in which autologous T cells are genetically modified to express a tumor-targeting chimeric antigen ...

Universitätsklinikum Würzburg

Immunotherapy with gene-engineered chimeric antigen receptor (CAR)-T cells has curative potential in advanced malignancies and undergoes a surging preclinical and clinical development. Here, we present a selection of new targets and technologies that illustrate the progress that is being made with the aspiration to make CAR-T cell therapy a universally applicable and effective treatment in cancer medicine.

New targets and technologies for CAR-T cells.

The microbiome is a complex host factor and key determinant of the outcome of antibody-based and cellular immunotherapy. Its postbiotics are a blend of soluble commensal byproducts that are released into the host environment and have been associated with the regulation of immune homeostasis, particularly through impacts on epigenetics and cell signaling. In this study, we show that the postbiotic pentanoate is metabolized to citrate within the TCA cycle via both the acetyl- and succinyl-CoA entry points, a feature uniquely enabled by the chemical structure of the C5 aliphatic chain. We identified ATP-citrate lyase as the crucial factor that redirects pentanoate-derived citrate from the succinyl-CoA route to the nucleus, thereby linking metabolic output and histone acetylation. This epigenetic-metabolic crosstalk mitigated T cell exhaustion and promoted naive-like differentiation in pentanoate-programmed chimeric antigen receptor (CAR) T cells. The predictive and therapeutic potential of pentanoate was corroborated in two independent patient cohorts and three syngeneic models of CAR T adoptive therapy. Our data demonstrate that postbiotics are integrated into mitochondrial metabolism and subsequently incorporated as epigenetic imprints. This bridge between microbial and mammalian interspecies communication can ultimately impact T cell differentiation and efficacy.

Article	Year
New targets and technologies for CAR-T cells. Current opinion in oncology\| PubMed ID: 32657796	2020
Metabolization of microbial postbiotic pentanoate drives anti-cancer CAR T cells. bioRxiv : the preprint server for biology\| PubMed ID: 39314273	2025

Fabian Freitag

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