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.
Subject(s)
Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/pathology , Matrix Metalloproteinase 2/metabolism , T-Lymphocytes, Regulatory/physiology , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Aged , Carcinoma, Squamous Cell/metabolism , Case-Control Studies , Cells, Cultured , Down-Regulation , Female , Humans , Lymphocytes, Tumor-Infiltrating/physiology , Male , Middle Aged , Muscle Neoplasms/immunology , Muscle Neoplasms/metabolism , Muscle Neoplasms/secondary , Neoplasm Invasiveness , Urinary Bladder Neoplasms/metabolismABSTRACT
Little is known on the role of distinct B-cell subtypes in human malignancies. We have recently performed a multiplex characterization of B cells in patient-derived tumor-associated tissues, documenting the activation and antigen-driven differentiation of B cells in metastatic lymph nodes and neoplastic lesions. Here we discuss the role of B lymphocytes as antigen-presenting cells and catalysts of T cell-based immunotherapies in view of these findings.
