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• W4387002185 abstract "ABSTRACTIntroduction Immune checkpoint inhibition (ICI) therapy has revolutionized the treatment of cancer. The principle of this treatment is that inhibitory molecules, either on the tumor or on cells of the immune system, are blocked by antibodies. The immune system of the patient subsequently should be able to attack and eradicate the tumor. Not all patients respond to ICI therapy, and response or non-response has been associated with composition of gut microbiota.Area covered Fecal microbiota transplantation (FMT) is used as adjunctive therapy in order to improve the outcome of ICI. Clinical Trials.gov, Clinical Trials in the European Union, Australian New Zealand Clinical Trials Registry, and the International Clinical Trials Registry Platform of the World Health Organization were searched (October 2022) for studies dealing with gut microbiota modification and the outcome of ICI.Expert opinion There is ample evidence for the beneficial effect of FMT on the outcome of ICI therapy for cancer, especially melanoma. The optimal treatment schedule, as well as donor selection criteria, still must be worked out. Progress is being made in the unraveling of the mechanisms by which microbiota and their metabolites (butyrate and the tryptophan metabolite indole-3-aldehyde) interact with the mucosal immune system of the host. A better understanding of these mechanisms contributes to improving FMT outcomes and developing novel therapeutic approaches. It will allow the identification of key bacterial species which mediate the effect of FMT. Promising species are Faecalibacterium prausnitzii, Eubacterium rectale, and three Bifidobacterium species (B. adolescentis, B.bifidum, and B. longum), because they are important direct and indirect butyrate producers, which could form the basis of targeted microbiota therapy.KEYWORDS: Butyratefecal microbiota transplantationimmune checkpoint inhibition therapyshort chain fatty acidstryptophanDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsImmune checkpoint inhibition (ICI) therapy, targeting CTLA-4 or PD-1 on T-lymphocytes and/or PD-L1 on tumor cells, has shown to be successful in a number of (metastasized) forms of cancer.Not all patients respond to ICI therapy and response or failure correlates with the composition of gut microbiota.In animal studies and in clinical trials, the combination of ICI with faecal microbiota transplantation (FMT) leads to a higher success rate.Selection of the ideal FMT donors as well as timing and frequency of FMT in combination with ICI therapy is currently under investigation in clinical trials.Identification of the relevant bacterial species as well as their metabolites is the focus of ongoing research.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Figure 1. Synergy between butyrate and immune checkpoint inhibition in immunotherapy of cancer. Panel A shows that intestinal microbiota can generate short chain fatty acids (including butyrate) from indigestible carbohydrates, such as food fibre. In panel B is shown that especially microbiota belonging to the phylum Firmicutes produce butyrate. The butyrate is used by epithelial cells as energy sources and also diffuses in underlying tissues. Butyrate acts as an inhibitor of histone deacetylases (HDAC). HDAC inhibition leads to activation of cytotoxic T lymphocytes (CTL) and of CD4+, FoxP3+ regulatory T cells (Treg). Inhibition of HDAC in tumor cells activates multiple anti-tumor pathways, including apoptosis and better stimulation of CTLs (panel C). In the tumor microenvironment (panel D) the increased CTL activity and the anti-tumor effects of HDAC inhibition can improve the outcome of immune checkpoint inhibition (anti-PD-L1 and anti-PD-1 indicated).Display full sizeFigure 2. Synergy between indole-3-aldehyde (I3A) and immune checkpoint inhibition in immunotherapy of cancer. Panel A shows that dietary tryptophan (Trp) can be metabolized into serotonin (and subsequently melatonin), by indoleamine 2,3-dioxygenases (IDO) into kynurenine, and by intestinal microbiota into I3A. In panel B is shown that especially Lactobacillus reuteri produces I3A from Trp. The I3A diffuses in underlying tissues, but it also has been shown that L. reuteri translocates to the tumor microenvironment, thus allowing for local I3A production. I3A is a ligand for aryl hydrocarbon receptor (AhR), an important cytosolic, transcription factor in cytotoxic T lymphocytes (CTL) (panel C). In the tumor microenvironment (panel D) the increased CTL activity can improve the outcome of immune checkpoint inhibition (anti-PD-L1 and anti-PD1 indicated).Display full sizeFigure 3. Visual representation of the design of ongoing clinical studies with immune checkpoint inhibition (ICI) therapy in combination with faecal microbiota transplantation (FMT). The studies are indicated by their registration number at ClinicalTrials.gov (as in Table 2) and ordered by the timepoint of the first FMT. Treatment schedule for the first 16 weeks is shown. The trials with a longer duration of intervention are indicated with a broken line. Trials from Table 2 which disclosed no information about timing and frequency of ICI treatment have been left out of this Figure. The studies indicated with an * use defined (consortia of) microbiota rather than full FMT.Display full sizeAdditional informationFundingThis paper received no funding." @default.
• W4387002185 created "2023-09-26" @default.
• W4387002185 creator A5010046770 @default.
• W4387002185 creator A5010698823 @default.
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• W4387002185 date "2023-09-25" @default.
• W4387002185 modified "2023-10-03" @default.
• W4387002185 title "The long and winding road of fecal microbiota transplants to targeted intervention for improvement of immune checkpoint inhibition therapy" @default.
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• W4387002185 doi "https://doi.org/10.1080/14737140.2023.2262765" @default.
• W4387002185 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37746903" @default.

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