Abstract
Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with 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 using 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 proinvasive 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 UBC 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. Cancer Immunol Res; 6(5); 528-38. ©2018 AACR.
Highlights
With their central role in immune regulation, regulatory T cells (Treg) have been implicated in a variety of diseases ranging from autoimmunity to malignancies
At the invasive front of urinary bladder cancer (UBC) tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation
CD4þFOXP3þ T cells accumulate in the tumor First, we examined and compared the respective T-cell populations extracted from the tumor and peripheral blood of patients undergoing transurethral resection of the bladder (TUR-B; n 1⁄4 46; for patient information, see Supplementary Table S1) and used peripheral blood from healthy donors as controls (n 1⁄4 11; gating strategy demonstrated in Supplementary Fig. S1A)
Summary
With their central role in immune regulation, regulatory T cells (Treg) have been implicated in a variety of diseases ranging from autoimmunity to malignancies. Given that antitumor T-cell responses represent a favorable prognostic factor, Tregs have long been considered unmitigated suppressors of antitumor immunity. This paradigm is being increasingly challenged: A meta-analysis concluded that a high Treg infiltration is negatively correlated to overall survival (OS) for the majority of. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
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