Research Insights – Using a gut-on-chip model to understand how SCFAs affect the function of CAR T cells

Learn in this blog how Valentin Wegner, researcher at Jena University Hospital, uses a Dynamic42-gut-on-chip model to understand how short-chain fatty acids (SCFAs) regulate the efficacy of CAR T cell function. This project is part of the imSAVAR consortium, with which he recently won a poster award at the annual EUROoCs conference in Milan.

CAR T cells: therapeutic advance in oncology

CAR (“chimeric antigen receptor”) T cell therapy is a cancer immunotherapy based on genetically modified T cells with synthetic antigen-specific receptors. CAR T cells recognize certain antigens (e.g. CD19) on the tumor cells and destroy them by their cytotoxic activity. The principle of CAR T cell therapy can be applied to all tumors that have well-defined antigen properties compared to healthy tissue. Although they are associated with severe side effects, CAR T cell therapies represent a major therapeutic advance in oncology.

Short-chain fatty acids and their significance for the CAR T cell therapy

SCFAs are a group of fatty acids with fewer than six carbon atoms. They are primarily produced through the fermentation of non-digestible, complex carbohydrates by bacteria in the colon. SCFAs play a crucial role in maintaining gut health and possess immunomodulatory potential in various autoimmune and inflammatory disease conditions [1].

Recent studies demonstrate that SCFAs can directly impact the efficacy of CAR T cell-based cancer immunotherapies [2]. Wegner and his colleagues from the University Hospital Würzburg and the Center for Sepsis Control and Care in Jena hypothesized that changes in serum SCFA levels caused by diet, antibiotics, or antitumor therapy such as radiation or chemotherapy, result in microbiome alterations and directly affect the efficacy and safety of CAR T cell therapy.

Using a Dynamic42-Organ-on-Chip model to show the impact of SCFAs

Wegner et al. performed their experiments in the Dynamic42-organ-on-chip (OoC) system of the gut, with microphysiological and immunocompetent properties [3]. It was built of an endothelium and an epithelium, both expressing the CAR T cell targeted ROR1 receptor. CAR T cells were pre-treated for 24 hours with the SCFAs acetate, propionate, butyrate and pentanoate and compared to untreated (CAR) T cells. To evaluate the effect of the CAR T cells, the tissue was stained for immunofluorescence imaging and supernatants were collected for cytokine analysis.

SCFAs clearly reduces tissue damage caused by CAR T cells

The study shows impressively that:

• • CAR T cells, in contrast to non-modified T cells, cause a high degree of tissue damage to the epithelial layer.
  • CAR T cells do not cause tissue damage if the OoC does not contain the target structure e.g. CD19.
  • The damage caused by the CAR-T cells is reduced when they are pre-treated with SCFAs. Acetate and pentanoate showed the least effect, while propionate and butyrate were more effective in protecting the tumor model from tissue damage.

Outlook

In further studies, the researchers from Jena and Würzburg plan to leverage the Dynamic42-gut-on-chip model to dissect individual contributing factors of SCFA-mediated host protection by analyzing the molecular mechanisms and T-cell phenotype changes induced by SCFAs and other microbial metabolites.

[1] A. Visekruna et al., Front Cell Dev Biol, vol. 9, p. 703218, 2021

[2] M. Luu et al., Nat Commun, vol. 12, no. 1, p. 4077, Jul 1, 2021

[3] M. Maurer et al., Biomaterials, vol. 220, p. 119396, Nov 2019

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