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Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness
Department of Medicine, Unit of Allergy and Immunology, Karolinska Institutet, Stockholm, Sweden.
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2018 (English)In: Cancer immunology research, ISSN 2326-6074, Vol. 6, no 5, p. 528-538Article in journal (Refereed) Published
Abstract [en]

Regulatory T cells (Tregs) have long been considered one-sided suppressors of antitumor immune responses and hence associated to poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by employing a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key pro-invasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and urinary bladder cancer cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC.

Place, publisher, year, edition, pages
2018. Vol. 6, no 5, p. 528-538
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Urology and Nephrology
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URN: urn:nbn:se:umu:diva-146190DOI: 10.1158/2326-6066.CIR-17-0466PubMedID: 29588320OAI: oai:DiVA.org:umu-146190DiVA, id: diva2:1194471
Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2018-06-09Bibliographically approved

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Zirakzadeh, Ali A .Rosenblatt, RobertVasko, JanosSherif, Amir

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