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Updated: Dec 22, 2025
Experimental Metastasis and CTL Adoptive Transfer Immunotherapy Mouse Model
Published on: November 26, 2010
Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer
Clélia Coutzac1,2,3,4, Jean-Mehdi Jouniaux1,2, Angelo Paci5,6,7
1Université Paris-Saclay, Institut Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Laboratoire d'Immunomonitoring en Oncologie, F-94805, Villejuif, France.
Abstract:
Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
Insights
High levels of short-chain fatty acids (SCFAs), like butyrate, in the blood are linked to reduced effectiveness of anti-CTLA-4 immunotherapy in cancer patients. These SCFAs appear to limit the immune response crucial for this cancer treatment.
Area of Science:
- Immunology
- Microbiology
- Oncology
Background:
- Gut microbiota influences cancer immunotherapy outcomes.
- Microbial metabolites, such as short-chain fatty acids (SCFAs), are proposed mediators.
- The specific role of SCFAs in anti-CTLA-4 therapy response is not fully understood.
Purpose of the Study:
- To investigate the relationship between SCFA levels and clinical outcomes in patients receiving anti-CTLA-4 therapy.
- To elucidate the molecular mechanisms by which SCFAs affect anti-CTLA-4 immune responses in preclinical models and patients.
Main Methods:
- Analysis of blood SCFA levels (butyrate, propionate) in mice and cancer patients treated with anti-CTLA-4.
- Assessment of immune cell populations (Treg, T cells) and activation markers (CD80/CD86, ICOS) in response to SCFA modulation.
- Measurement of cytokine levels (IL-2) in patients.
Main Results:
- High blood butyrate and propionate levels correlated with resistance to CTLA-4 blockade and increased regulatory T cell (Treg) proportion.
- In mice, butyrate inhibited anti-CTLA-4-mediated immune cell activation and tumor-specific T cell accumulation.
- In patients, high butyrate levels were associated with reduced ipilimumab-induced T cell expansion and IL-2 levels.
Conclusions:
- SCFAs, particularly butyrate, limit the efficacy of anti-CTLA-4 immunotherapy.
- Targeting SCFA production or signaling could potentially enhance anti-CTLA-4 therapy outcomes in cancer.
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