Uterine Commensal Peptostreptococcus Species Contribute to IDO1 Induction in Endometrial Cancer via Indoleacrylic Acid

Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the involvement of the female genital tract Peptostreptococcus species in gynecological cancer via indoleacrylic acid (IAA). IAA production from Peptostreptococcus species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on Treg and Teff cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically, Peptostreptococcus species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by Peptostreptococcus species transplantation, and the intratumoral injection of a conditioned medium from Peptostreptococcus cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the Treg proportion and decreased the M1/M2 ratio. Clinically, P. anaerobius was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine Peptostreptococcus dysbiosis and provides a potential rationale for the role of Peptostreptococcus species in immune tolerance induction in type I endometrial cancer.

[1]  Supratim Mandal,et al.  Human microbial dysbiosis as driver of gynecological malignancies. , 2022, Biochimie.

[2]  J. Brosens,et al.  Chromosomally normal miscarriage is associated with vaginal dysbiosis and local inflammation , 2022, BMC Medicine.

[3]  D. Zang,et al.  The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy , 2021, Frontiers in Oncology.

[4]  M. Jenab,et al.  The Role of Gut Barrier Dysfunction and Microbiome Dysbiosis in Colorectal Cancer Development , 2021, Frontiers in Oncology.

[5]  R. Chatterjee,et al.  Dysbiosis of Oral Microbiota During Oral Squamous Cell Carcinoma Development , 2021, Frontiers in Oncology.

[6]  L. Brubaker,et al.  Vaginal Estrogen Therapy Is Associated with Increased Lactobacillus in the Urine of Post-Menopausal Women with Overactive Bladder Symptoms. , 2020, American journal of obstetrics and gynecology.

[7]  J. H. van de Wijgert,et al.  Pathobionts in the Vaginal Microbiota: Individual Participant Data Meta-Analysis of Three Sequencing Studies , 2020, Frontiers in Cellular and Infection Microbiology.

[8]  Z. Ilhan,et al.  The microbiome and gynaecological cancer development, prevention and therapy , 2020, Nature Reviews Urology.

[9]  L. Zeng,et al.  Asparagine Synthetase and Filamin A Have Different Roles in Ovarian Cancer , 2019, Front. Oncol..

[10]  M. Neurath.  Targeting immune cell circuits and trafficking in inflammatory bowel disease , 2019, Nature Immunology.

[11]  Siqi Liu,et al.  Interleukin-35 modulates the balance between viral specific CD4+CD25+CD127dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection , 2019, Virology Journal.

[12]  A. Rosenwald,et al.  Prognostic value of tumour-infiltrating CD8+ lymphocytes in rectal cancer after neoadjuvant chemoradiation: is indoleamine-2,3-dioxygenase (IDO1) a friend or foe? , 2019, Cancer Immunology, Immunotherapy.

[13]  R. Weissleder,et al.  Arg1 expression defines immunosuppressive subsets of tumor-associated macrophages , 2018, Theranostics.

[14]  Yuanyuan Shi,et al.  Mechanism and prognostic value of indoleamine 2,3‐dioxygenase 1 expressed in hepatocellular carcinoma , 2018, Cancer science.

[15]  T. Nomura,et al.  The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis , 2018, Nature Immunology.

[16]  Nand K. Singh,et al.  Regulatory T Cells and Their Association with Serum Markers and Symptoms in Systemic Lupus Erythematosus and Rheumatoid Arthritis , 2018, Immunological investigations.

[17]  G. Kenter,et al.  Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer , 2018, Frontiers in Immunology.

[18]  G. Georgiou,et al.  Reversal of IDO-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme , 2018, Nature Biotechnology.

[19]  S. Brady,et al.  Accessing Bioactive Natural Products from the Human Microbiome. , 2018, Cell host & microbe.

[20]  Yuanmin Qian,et al.  Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma , 2018, Cancer science.

[21]  Huijue Jia,et al.  The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases , 2017, Nature Communications.

[22]  G. Minkov,et al.  Increased Circulating CD4+CD25+CD127low/neg Regulatory T-cells as a Prognostic Biomarker in Acute Pancreatitis. , 2017, Pancreas.

[23]  Jun Yu,et al.  Mucosal microbiome dysbiosis in gastric carcinogenesis , 2017, Gut.

[24]  Daniel J. O'Connell,et al.  Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation. , 2017, Cell host & microbe.

[25]  Daniel M. Corey,et al.  PD-1 expression by tumor-associated macrophages inhibits phagocytosis and tumor immunity , 2017, Nature.

[26]  James L. Richards,et al.  Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes , 2017, Nature Immunology.

[27]  A. Mariani,et al.  Potential contribution of the uterine microbiome in the development of endometrial cancer , 2016, Genome Medicine.

[28]  L. Zitvogel,et al.  Microbiome and Anticancer Immunosurveillance , 2016, Cell.

[29]  N. Abu-Rustum,et al.  Endometrial cancer , 2016, The Lancet.

[30]  R. Fichorova,et al.  The Human Microbiome during Bacterial Vaginosis , 2016, Clinical Microbiology Reviews.

[31]  Ron Milo,et al.  Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans , 2016, Cell.

[32]  B. J. Van den Eynde,et al.  Tumoral Immune Resistance Mediated by Enzymes That Degrade Tryptophan , 2015, Cancer Immunology Research.

[33]  D. Tyler,et al.  Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy , 2015, Cancer Immunology Research.

[34]  Melis N. Anahtar,et al.  Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. , 2015, Immunity.

[35]  Wendy S. Garrett,et al.  Cancer and the microbiota , 2015, Science.

[36]  S. Sarin,et al.  CD4+CD25+CD127low Regulatory T Cells Play Predominant Anti-Tumor Suppressive Role in Hepatitis B Virus-Associated Hepatocellular Carcinoma , 2015, Front. Immunol..

[37]  H. Flint,et al.  The gut microbiota, bacterial metabolites and colorectal cancer , 2014, Nature Reviews Microbiology.

[38]  G. Prendergast,et al.  Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer , 2014, Cancer Immunology, Immunotherapy.

[39]  Xiaomei Li,et al.  CD4+CD25+CD127low/− T Cells: A More Specific Treg Population in Human Peripheral Blood , 2012, Inflammation.

[40]  M. Plummer,et al.  Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. , 2012, The Lancet. Oncology.

[41]  T. Mcclanahan,et al.  IL-10 elicits IFNγ-dependent tumor immune surveillance. , 2011, Cancer Cell.

[42]  P. Gajer,et al.  Vaginal microbiome of reproductive-age women , 2010, Proceedings of the National Academy of Sciences.

[43]  L. Moretta,et al.  The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. , 2006, Blood.

[44]  H. Kajiyama,et al.  Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer , 2006, British Journal of Cancer.

[45]  G. Minkov,et al.  Increased Circulating CD4+CD25+CD127low/neg Regulatory T-cells as a Prognostic Biomarker in Acute Pancreatitis. , 2017, Pancreas.