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Published on: April 21, 2015
Short-Chain Fatty Acids Modulate Anti-ROR1 CAR T-Cell Function and Exhaustion in an Intestinal Adenocarcinoma-on-Chip
Valentin D Wegner1, Adrian Feile1, Miriam Alb2,3
1Institute of Biochemistry II, Jena University Hospital, 07747, Jena, Germany.
Abstract:
Chimeric antigen receptor (CAR) T-cell therapy represents a promising approach for cancer treatment, with receptor tyrosine kinase-like orphan receptor 1 (ROR1) emerging as a novel target in malignancies. This study investigates how short-chain fatty acids (SCFAs), key microbiota-derived metabolites, modulate anti-ROR1 CAR T-cell efficacy using a physiologically relevant intestinal adenocarcinoma-on-chip model that replicates the human intestinal microenvironment. The findings demonstrate that propionate and butyrate inhibit anti-ROR1 CAR T-cell function by reducing infiltration, cytotoxicity, and cytokine release while preserving junctional integrity within the tumor model. Mechanistically, these SCFAs inhibit histone deacetylase activity and promote a phenotype switch toward regulatory T-cells, as indicated by increased expression of FoxP3 and RORγt. Additionally, propionate and butyrate upregulate PD-1 and TIM-3, markers of T-cell exhaustion and immune tolerance, and induce a dose- and time-dependent reduction in proinflammatory cytokines. In contrast, acetate and pentanoate promote a proinflammatory T helper 17 phenotype. These results highlight the immunomodulatory effects of SCFAs on CAR T-cell function, emphasizing the need to consider microbiota-derived metabolites in CAR T-cell therapies.
Insights
Short-chain fatty acids (SCFAs) like propionate and butyrate can hinder chimeric antigen receptor (CAR) T-cell therapy effectiveness against ROR1-expressing cancers by promoting T-cell exhaustion and reducing anti-tumor activity.
Area of Science:
- Immunology
- Oncology
- Microbiome research
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is a promising cancer treatment.
- Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a novel target in various malignancies.
- Microbiota-derived short-chain fatty acids (SCFAs) can influence immune responses.
Purpose of the Study:
- To investigate the impact of SCFAs on anti-ROR1 CAR T-cell efficacy.
- To utilize a human intestinal adenocarcinoma-on-chip model to simulate the tumor microenvironment.
- To elucidate the mechanisms by which SCFAs modulate CAR T-cell function.
Main Methods:
- Employing a human intestinal adenocarcinoma-on-chip model.
- Assessing CAR T-cell infiltration, cytotoxicity, and cytokine release.
- Analyzing T-cell phenotype, gene expression (FoxP3, RORγt), and immune checkpoint markers (PD-1, TIM-3).
- Evaluating the effect of SCFAs (propionate, butyrate, acetate, pentanoate) on T-cell function and tumor microenvironment.
Main Results:
- Propionate and butyrate inhibited anti-ROR1 CAR T-cell infiltration, cytotoxicity, and cytokine release.
- These SCFAs promoted a regulatory T-cell phenotype by inhibiting histone deacetylase activity and upregulating FoxP3 and RORγt.
- Propionate and butyrate increased PD-1 and TIM-3 expression, indicating T-cell exhaustion.
- Acetate and pentanoate promoted a T helper 17 proinflammatory phenotype.
- SCFAs demonstrated dose- and time-dependent effects on cytokine production and T-cell function.
Conclusions:
- SCFAs, particularly propionate and butyrate, can negatively modulate anti-ROR1 CAR T-cell efficacy.
- The mechanisms involve promoting T-cell exhaustion and a shift towards regulatory T-cells.
- Microbiota-derived metabolites are crucial factors to consider for optimizing CAR T-cell therapies.
- Understanding SCFA effects is vital for developing strategies to enhance CAR T-cell therapy outcomes in ROR1-positive cancers.
