Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite
Background Despite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manag...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003725.full |
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| author | Giorgia Renga Emilia Nunzi Marilena Pariano Matteo Puccetti Marina Maria Bellet Giuseppe Pieraccini Fiorella D’Onofrio Ilaria Santarelli Claudia Stincardini Franco Aversa Francesca Riuzzi Cinzia Antognelli Marco Gargaro Oxana Bereshchenko Maurizio Ricci Stefano Giovagnoli Luigina Romani Claudio Costantini |
| author_facet | Giorgia Renga Emilia Nunzi Marilena Pariano Matteo Puccetti Marina Maria Bellet Giuseppe Pieraccini Fiorella D’Onofrio Ilaria Santarelli Claudia Stincardini Franco Aversa Francesca Riuzzi Cinzia Antognelli Marco Gargaro Oxana Bereshchenko Maurizio Ricci Stefano Giovagnoli Luigina Romani Claudio Costantini |
| author_sort | Giorgia Renga |
| collection | DOAJ |
| description | Background Despite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manageable side effects to existing ICIs would enhance and expand their therapeutic efficacy and application. Due to its proven role in cancer development and immune regulation, gut microbiome has gained increasing expectation as a potential armamentarium to optimize immunotherapy with ICI. However, much has to be learned to fully harness gut microbiome for clinical applicability. Here we have assessed whether microbial metabolites working at the interface between microbes and the host immune system may optimize ICI therapy.Methods To this purpose, we have tested indole-3-carboxaldehyde (3-IAld), a microbial tryptophan catabolite known to contribute to epithelial barrier function and immune homeostasis in the gut via the aryl hydrocarbon receptor (AhR), in different murine models of ICI-induced colitis. Epithelial barrier integrity, inflammation and changes in gut microbiome composition and function were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 and IL-22 knockout mice were used to investigate the mechanism of 3-IAld activity. The function of the microbiome changes induced by 3-IAld was evaluated on fecal microbiome transplantation (FMT). Finally, murine tumor models were used to assess the effect of 3-IAld treatment on the antitumor activity of ICI.Results On administration to mice with ICI-induced colitis, 3-IAld protected mice from intestinal damage via a dual action on both the host and the microbes. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that FMT from 3-IAld-treated mice protected against ICI-induced colitis with the contribution of butyrate-producing bacteria. Importantly, while preventing intestinal damage, 3-IAld did not impair the antitumor activity of ICI.Conclusions This study provides a proof-of-concept demonstration that moving past bacterial phylogeny and focusing on bacterial metabolome may lead to a new class of discrete molecules, and that working at the interface between microbes and the host immune system may optimize ICI therapy. |
| format | Article |
| id | doaj-art-aa66edc0424440c1996cf3545f2794c4 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-aa66edc0424440c1996cf3545f2794c42025-08-20T03:05:22ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003725Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metaboliteGiorgia Renga0Emilia Nunzi1Marilena Pariano2Matteo Puccetti3Marina Maria Bellet4Giuseppe Pieraccini5Fiorella D’Onofrio6Ilaria Santarelli7Claudia Stincardini8Franco Aversa9Francesca Riuzzi10Cinzia Antognelli11Marco Gargaro12Oxana Bereshchenko13Maurizio Ricci14Stefano Giovagnoli15Luigina Romani16Claudio Costantini171 Department of Medicine and Surgery, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy2 Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy3 Department of Health Sciences, University of Florence, Firenze, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy4 Department of Medicine and Surgery, University of Parma, Parma, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy5 Department of Philosophy, Social Sciences and Education, University of Perugia, Perugia, Italy2 Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy2 Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, Italy1 Department of Medicine and Surgery, University of Perugia, Perugia, ItalyBackground Despite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manageable side effects to existing ICIs would enhance and expand their therapeutic efficacy and application. Due to its proven role in cancer development and immune regulation, gut microbiome has gained increasing expectation as a potential armamentarium to optimize immunotherapy with ICI. However, much has to be learned to fully harness gut microbiome for clinical applicability. Here we have assessed whether microbial metabolites working at the interface between microbes and the host immune system may optimize ICI therapy.Methods To this purpose, we have tested indole-3-carboxaldehyde (3-IAld), a microbial tryptophan catabolite known to contribute to epithelial barrier function and immune homeostasis in the gut via the aryl hydrocarbon receptor (AhR), in different murine models of ICI-induced colitis. Epithelial barrier integrity, inflammation and changes in gut microbiome composition and function were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 and IL-22 knockout mice were used to investigate the mechanism of 3-IAld activity. The function of the microbiome changes induced by 3-IAld was evaluated on fecal microbiome transplantation (FMT). Finally, murine tumor models were used to assess the effect of 3-IAld treatment on the antitumor activity of ICI.Results On administration to mice with ICI-induced colitis, 3-IAld protected mice from intestinal damage via a dual action on both the host and the microbes. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that FMT from 3-IAld-treated mice protected against ICI-induced colitis with the contribution of butyrate-producing bacteria. Importantly, while preventing intestinal damage, 3-IAld did not impair the antitumor activity of ICI.Conclusions This study provides a proof-of-concept demonstration that moving past bacterial phylogeny and focusing on bacterial metabolome may lead to a new class of discrete molecules, and that working at the interface between microbes and the host immune system may optimize ICI therapy.https://jitc.bmj.com/content/10/3/e003725.full |
| spellingShingle | Giorgia Renga Emilia Nunzi Marilena Pariano Matteo Puccetti Marina Maria Bellet Giuseppe Pieraccini Fiorella D’Onofrio Ilaria Santarelli Claudia Stincardini Franco Aversa Francesca Riuzzi Cinzia Antognelli Marco Gargaro Oxana Bereshchenko Maurizio Ricci Stefano Giovagnoli Luigina Romani Claudio Costantini Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite Journal for ImmunoTherapy of Cancer |
| title | Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite |
| title_full | Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite |
| title_fullStr | Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite |
| title_full_unstemmed | Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite |
| title_short | Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite |
| title_sort | optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite |
| url | https://jitc.bmj.com/content/10/3/e003725.full |
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