Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness

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 ( = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4FOXP3 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. .

Clinical impact of T cells, B cells and the PD-1/PD-L1 pathway in muscle invasive bladder cancer: a comparative study of transurethral resection and cystectomy specimens

“…Tregs have long been viewed as arrant immunosuppressors and are thus expected to be associated with a dismal prognosis. 16 Indeed, a meta-analysis by Shang et al concluded that high Treg infiltration was negatively correlated with survival in most studied solid tumors. 31 Nonetheless, a paradoxical positive prognostic impact of Tregs has been reported in studies on colorectal, oesophageal, head and neck as well as bladder cancer.…”

“…31 Nonetheless, a paradoxical positive prognostic impact of Tregs has been reported in studies on colorectal, oesophageal, head and neck as well as bladder cancer. 16,31 One proposed explanation for these observations is that infiltration of Tregs may reflect an ongoing CD8 + CTL response. 31 Moreover, Winerdal et al have recently described that the positive prognostic influence of FoxP3 + Tregs on bladder cancer survival could be explained by a Treg mediated restriction of cancer progression, through downregulation of tumor matrix metalloproteinase 2 (MMP2), a key pro-invasive factor.…”

“…31 Moreover, Winerdal et al have recently described that the positive prognostic influence of FoxP3 + Tregs on bladder cancer survival could be explained by a Treg mediated restriction of cancer progression, through downregulation of tumor matrix metalloproteinase 2 (MMP2), a key pro-invasive factor. 16 This finding implies that the regulatory T cell population could have other than solely immunosuppressive intrinsic functions, which may in part explain their varying relationship with prognosis, depending on the cancer type. Most of the literature on cell-mediated anti-tumor responses have been focused on T lymphocytes, while only a few studies have investigated the contribution of the B cell lineage in MIBC.…”

“…14,15 Similarly, infiltration of other T cell subsets, including Forkhead box P3 + (FoxP3 + ) Tregs, has been correlated with an improved survival. 16 A reinforced anti-tumor T cell response in lymph nodes after NAC treatment in MIBC has recently been demonstrated by Krantz et al 17 Apart from the T cell response, B cells also play a critical role in anti-tumor immunity and lymphoplasmacytic infiltration has been linked to favorable outcomes in several cancer types, including colorectal cancer, breast, cervical and non-small cell lung cancer. [18][19][20] As of yet, the prognostic significance of tumor-infiltrating cells of the B lineage, including CD20 + B lymphocytes, in MIBC is poorly understood.…”

lncRNA SNHG1 Promotes Basal Bladder Cancer Invasion via Interaction with PP2A Catalytic Subunit and Induction of Autophagy

“… 53 , 54 , 55 , 56 Our previous studies and many other studies have proved that MMP2 could enhance MIBC invasion. 57 , 58 However, the mechanism of maintenance of MMP2 abundance is still unclear in the basal MIBC. Based on the results obtained from studies here, overexpression of SNHG1 significantly increased MMP2 protein levels, leading to enhanced basal MIBC cell-invasive activities.…”