Prediction of intravesical recurrence of non-muscle-invasive bladder cancer by evaluation of intratumoral Foxp3+ T cells in the primary transurethral resection of bladder tumor specimens

Murai, Ryosuke; Itoh, Yasushi; Kageyama, Susumu; Nakayama, Misako; Ishigaki, Hirohito; Teramoto, Koji; Narita, Mitsuhiro; Yoshida, Tetsuya; Tomita, Kengo; Kobayashi, Kenichi; Wada, Akinori; Nagasawa, Mitsuru; Kubota, Shigehisa; Ogasawara, Kunio; Kawauchi, Akihiro

doi:10.1371/journal.pone.0204745

Cited by 25 publications

(28 citation statements)

References 21 publications

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“…To assess other candidate immune-suppressive cells that could be altered by IL-2c, we undertook initial studies of Tregs and myeloid-derived suppressor cells (MDSCs), both of which are detrimental in human BC 40 41 and we previously reported that Tregs affect MB49 BC growth in bladder more than lung. 42 In our studies of IL-2c mechanisms in ovarian cancer, we found that IL-2c induces fragile Tregs with reduced suppressive function which are identified by maintained FoxP3 expression, and upregulated IFN-γ, T-bet, and PD-1.…”

Section: Resultsmentioning

confidence: 99%

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

Reyes

Deng

Zhang

et al. 2021

J Immunother Cancer

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BackgroundAnti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+ antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+ mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.ResultsIL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+ T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+ T cells but not γδ T cells.ConclusionsMechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.

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Section: Resultsmentioning

confidence: 99%

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

Reyes

Deng

Zhang

et al. 2021

J Immunother Cancer

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“…In fact, blocking IL-10 and TGFβ has been shown to reduce the induction of CD25+ve regulatory T cells in vitro by a bladder cancer cell line (26). Such Tregs are capable of suppressing immune responses to cancer, often through their suppression of cytotoxic T cells and constitute a significant percentage of TILs in bladder cancer- a median of 17% across samples in one study (99). However, a clear role for regulatory T cells in bladder cancer is unclear with some studies suggesting a positive correlation with clinical outcomes.…”

Section: Foxp3 Regulatory Cells and Th17 Helper T Cellsmentioning

confidence: 99%

“…However, numerous studies have found negative correlations between FoxP3 T regulatory cells and survival including one study of 115 cases of NMIBC which found an inverse correlation between FoxP3 cell frequency within the tumor (as % of CD3+ve cells) and recurrence-free survival (99). Additionally, higher FoxP3 infiltration in the stroma around the tumor was shown to predict a shorter recurrence free survival post-BCG treatment for NMIBC (102).…”

Section: Foxp3 Regulatory Cells and Th17 Helper T Cellsmentioning

confidence: 99%

Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

Joseph

Enting

2019

Front. Oncol.

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Immunosurveillance, which describes the immunologically mediated elimination of transformed cells, has been widely accepted in the context of bladder cancer for many decades with the successful use of Bacillus-Calmette Guerin for superficial bladder cancer since the 1970s. With the emergence of checkpoint inhibitor blockade in the treatment of urothelial cancers, there has been a resurgent interest in the immunology of bladder cancer. The theory of cancer immunoediting proposes that the immune system has both pro-tumorigenic and anti-tumor effects, the balance between the two determining the progression of an individual tumor. However, whilst there is evidence for the action of various immune cell populations in bladder cancer, a cohesive picture of the immune response to bladder cancer and its driving forces are still lacking. Additionally, little is still known about the normal immune landscape of the bladder. Future progress in bladder cancer therapeutic approaches will require a strong foundation in understanding the immunology of this disease. This review considers the evidence for the role of the main immune cell populations, both innate and adaptive, in the immune response to bladder cancer. Recent research and overarching themes in the immune response to bladder cancer are explored. The minimal evidence regarding the normal immune landscape of the human bladder is also summarized to contextualize downstream immune responses. Of specific interest are the innate and myeloid populations, some of which are resident in the human bladder and which have significant effects on downstream adaptive tumor immunity. We discuss factors which restrain the efficacy of populations known to have anti-tumor activity such as cytotoxic T cells, including the constraints on checkpoint blockade. Additionally, the effects on the immune response of tumor intrinsic factors such as the genomic subtype of bladder cancer and the effect of common therapies such as chemotherapy and intravesical Bacillus Calmette-Guerin are considered. A significant theme is the polarization of immune responses within the tumor by a heavily immunosuppressive tumor microenvironment which affects the phenotype of multiple innate and adaptive populations. Throughout, clinical implications are discussed with suggestions for future research directions and therapeutic targeting.

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“…Of those survived full-text assessment, 3 were excluded for not clearly describing staining methods and one study was excluded because there was only one research on CD4+ lymphocytes, which provided limited values. Finally 14 studies were enrolled in this metaanalysis and the study characteristics are shown in Table 1 (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). All studies investigated TILs by immunohistochemistry or hematoxylin-and eosin (H&E)-stained sections in paraffin-embedded tissue.…”

Section: Study Selection and Characteristicsmentioning

confidence: 99%

The prognostic role of tumor-infiltrating lymphocytes in urothelial carcinoma of bladder: A systematic review and meta-analysis

Yang¹,

Bai²,

Hu³

et al. 2020

Preprint

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Background: Tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment are associated with different prognosis in various malignancies. However, their prognostic impact remains controversial in urothelial carcinoma of bladder (UCB). In this systematic review and meta-analysis, we aimed to investigate the prognostic value of TILs in UCB patients.Methods: A systematic review and meta-analysis was performed using Pubmed, Embase and Cochrane Library. Studies were eligible if they investigated the prognostic value of CD3+, CD4+, CD8+, Foxp3+ lymphocytes or TILs in UCB patients, by time-to-event survival analysis. All studies were appraised for risk of bias using the Quality and Prognosis Studies (QUIPS) criteria. Hazard rations (HRs) with their 95% confidence interval (CIs) from each study were used to generate pooled HRs. Results: A total of 14 studies assessing the impact of TILs on prognostic outcomes in UCB patients were included in final analysis. The pooled analysis indicated a favorable role of CD3+ TILs (HR 0.74 (95% CI 0.62-0.88) for overall survival) and CD8+ TILs (HR 0.46 (95% CI 0.28-0.74) for OS) in the clinical outcomes of UCB, while Foxp3+ TILs were associated with worse survival (HR 2.21 (95% CI 1.47-3.32) for recurrence-free survival). Conclusions: This systematic review and meta-analysis confirmed the favorable prognostic impact of CD3+ and CD8+ tumor-infiltrating T cells in UCB patients and found the association between Foxp3+ TILs and worse survival. Future studies using large cohorts and standardized methodology with regard to tumor subsites, stages and treatment modalities are needed to incorporate TILs with clinical practice.

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Prediction of intravesical recurrence of non-muscle-invasive bladder cancer by evaluation of intratumoral Foxp3+ T cells in the primary transurethral resection of bladder tumor specimens

Cited by 25 publications

References 21 publications

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

The prognostic role of tumor-infiltrating lymphocytes in urothelial carcinoma of bladder: A systematic review and meta-analysis

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