Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity

Hezaveh, Kebria; Shinde, Rahul; Klötgen, Andreas; Halaby, Marie Jo; Lamorte, Sara; Ciudad, Marion; Quevedo, Rene; Neufeld, Luke; Liu, Zhe Qi; Jin, Robbie; Grünwald, Barbara; Foerster, Elisabeth G.; Chaharlangi, Danica; Guo, Mengdi; Makhijani, Priya; Zhang, Xin; Pugh, Trevor J.; Pinto, Devanand M.; Co, Ileana L.; McGuigan, Alison P.; Jang, Gun Ho; Khokha, Rama; Ohashi, Pamela S.; O’Kane, Grainne M.; Gallinger, Steven; Navarre, William Wiley; Maughan, Heather; Philpott, Dana J.; Brooks, David G.; McGaha, Tracy L.

doi:10.1016/j.immuni.2022.01.006

Cited by 293 publications

(212 citation statements)

References 69 publications

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“…These agonists modulate the functions of many cell types such as epithelial cells, immune cells and astrocytes, both locally and systemically ( 143 , 144 ). Although recent studies show that tryptophan-derived microbial metabolites suppress anti-tumor immunity by activating AhR in tumor-associated macrophages ( 145 ), data are lacking to determine whether tryptophan-derived metabolites are implicated in H pylori -induced reduction of cancer immunotherapies ( 146 ).…”

Section: Is the H Pylori -Induced Decrease In Effi...mentioning

confidence: 99%

The Efficacy of Cancer Immunotherapies Is Compromised by Helicobacter pylori Infection

et al. 2022

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Helicobacter pylori infects the gastric mucosa of a large number of humans. Although asymptomatic in the vast majority of cases, H pylori infection can lead to the development of peptic ulcers gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Using a variety of mechanisms, H pylori locally suppresses the function of the host immune system to establish chronic infection. Systemic immunomodulation has been observed in both clinical and pre-clinical studies, which have demonstrated that H pylori infection is associated with reduced incidence of inflammatory diseases, such as asthma and Crohn’s disease. The introduction of immunotherapies in the arsenal of anti-cancer drugs has revealed a new facet of H pylori-induced immune suppression. In this review, we will describe the intimate interactions between H pylori and its host, and formulate hypothtyeses describing the detrimental impact of H pylori infection on the efficacy of cancer immunotherapies.

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Section: Is the H Pylori -Induced Decrease In Effi...mentioning

confidence: 99%

The Efficacy of Cancer Immunotherapies Is Compromised by Helicobacter pylori Infection

et al. 2022

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“…Amino acid metabolism plays an important role in regulating anticancer immunity in many cancers. As the previous studies found, the metabolites of tryptophan Evidence-Based Complementary and Alternative Medicine metabolism supported tumor-associated macrophages to facilitate immunosuppression in pancreatic cancer [19]. High levels of arginase that catalyze the L-arginine can inhibit the proliferation of antigen-specific T cells in lung cancer [20].…”

Section: Discussionmentioning

confidence: 85%

Identification of an Amino Acid Metabolism Signature Participating in Immunosuppression in Ovarian Cancer

Yang

2022

Evidence-Based Complementary and Alternative Medicine

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Ovarian cancer is one of the most fatal gynecologic cancer types, and its heterogeneity in the microenvironment limited the efficacy of the current treatment. In this study, we aimed at building a risk score to predict patient survival based on the amino acid metabolic genes and TCGA RNA-seq dataset (n = 376). We first used univariate analysis and PCA to select and test the survival-related genes, and the LASSO regression was applied to build the risk score signature with prediction accuracy estimation by survival analysis and ROC. We then conducted GSEA and GSVA to investigate the biological roles of the signature and run ESTIMATE and 4 different immunocyte infiltration algorithms to investigate the immunological diversity between the risk groups. Furthermore, the immune checkpoint expression was compared. We finally explored the cMap and PRISM database to screen out sensitive drugs for high-risk patients and analyzed the oncogenic role of TPH1 by clone formation and transwell migration assays. As a result, the risk score predicted patients’ survival and stage with high accuracy. We found that the signature mainly affected the extracellular activities and cancer immunity by functional enrichment. We further discovered that the high-risk OV harbored a high level of stromal cell infiltration and was associated with highly infiltrated fibroblasts and decreased CD8+ T cells. The immune checkpoint analyses showed that TGFB1 and CD276 were upregulated. Finally, we screened out 4 PRISM drugs with lower IC50 in the high-risk group and validated the oncogenic role of TPH1 in OV cancers. We believe this research offered a novel understanding of the interplay between amino acid metabolism and immunity in OV and will benefit patients with better prognostic management and therapeutic strategy development.

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“…Also, M2 macrophages enhance the expression of PD-L1 in TME, potentially Reply to reviewer #suppressing the response to ICIs [ 85 ]. Moreover, tryptophan metabolism by intestinal microbiota induces the immunosuppressive phenotype of TAMs, most likely related to accelerated progression and high mortality rate in pancreatic ductal adenocarcinoma (PDAC) [ 86 ].…”

Section: Gut Microbiota and Anti-tumor Immunitymentioning

confidence: 99%

The Effect of the Gut Microbiota on Systemic and Anti-Tumor Immunity and Response to Systemic Therapy against Cancer

Aghamajidi

Vareki

2022

Cancers

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Gut microbiota can have opposing functions from pro-tumorigenic to anti-tumorigenic effects. Increasing preclinical and clinical evidence suggests that the intestinal microbiota affects cancer patients’ response to immune checkpoint inhibitors (ICIs) immunotherapy, such as anti-programmed cell death protein 1 (PD-1) and its ligand (PD-L1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Microbiota-induced inflammation possibly contributes to tumor growth and cancer development. Microbiota-derived metabolites can also be converted to carcinogenic agents related to genetic mutations and DNA damage in organs such as the colon. However, other attributes of microbiota, such as greater diversity and specific bacterial species and their metabolites, are linked to better clinical outcomes and potentially improved anti-tumor immunity. In addition, the intratumoral microbial composition strongly affects T-cell-mediated cytotoxicity and anti-tumor immune surveillance, adding more complexity to the cancer-microbiome-immune axis. Despite the emerging clinical evidence for the activity of the gut microbiota in immuno-oncology, the fundamental mechanisms of such activity are not well understood. This review provides an overview of underlying mechanisms by which the gut microbiota and its metabolites enhance or suppress anti-tumor immune responses. Understanding such mechanisms allows for better design of microbiome-specific treatment strategies to improve the clinical outcome in cancer patients undergoing systemic therapy.

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Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity

Cited by 293 publications

References 69 publications

The Efficacy of Cancer Immunotherapies Is Compromised by Helicobacter pylori Infection

The Efficacy of Cancer Immunotherapies Is Compromised by Helicobacter pylori Infection

Identification of an Amino Acid Metabolism Signature Participating in Immunosuppression in Ovarian Cancer

The Effect of the Gut Microbiota on Systemic and Anti-Tumor Immunity and Response to Systemic Therapy against Cancer

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