• PD-L1
• basal
• bladder cancer
• immunotherapy
• luminal
• molecular subtypes

• Humans
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/mortality
• Urinary Bladder Neoplasms/immunology
• Urinary Bladder Neoplasms/metabolism
• B7-H1 Antigen/metabolism
• Tumor Microenvironment/immunology
• Male
• Female
• Aged
• Middle Aged
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Prognosis
• Aged, 80 and over
• Lymphocytes, Tumor-Infiltrating/immunology
• Adult
• Immunohistochemistry
• Neoplasm Invasiveness

• A-705 Research Section, All India Institute of Medical Sciences, New Delhi

• IL- 10 + TAMs
• Immune checkpoints
• Monocytes
• Tumor associated macrophages
• Urothelial Carcinoma of Bladder

• Humans
• Urinary Bladder Neoplasms/immunology
• Urinary Bladder Neoplasms/pathology
• Male
• Female
• Monocytes/immunology
• Monocytes/metabolism
• Tumor-Associated Macrophages/immunology
• Tumor-Associated Macrophages/metabolism
• Middle Aged
• Aged
• Phenotype
• Adult
• Tumor Microenvironment
• Immunophenotyping

• 09/006(0521)/2020-EMR-I) Council for Scientific and Industrial Research (CSIR) India

• anti-CTLA-4
• anti-PD-1/PD-L1
• immune checkpoint inhibitors
• immunotherapy
• tumor microenvironment

• SOX13
• THCA
• biomarker
• ferroptosis
• genetic alterations
• tumor-immune infiltration

• Humans
• Ferroptosis/genetics
• Ferroptosis/immunology
• Thyroid Neoplasms/immunology
• Thyroid Neoplasms/pathology
• Thyroid Neoplasms/genetics
• Thyroid Neoplasms/metabolism
• Cell Proliferation
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Prognosis
• Cell Movement
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Female
• Neoplasm Metastasis
• Male
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Middle Aged

• Bladder cancer
• Chemoresistance
• Nanoparticles
• Prostate cancer
• Renal cancer
• Wnt

• Immune cells
• Muscle-invasive urothelial bladder cancer
• Prevalence of PD-L1 expression
• Tumor biomarkers
• Tumor cells
• Tumor mutation burden

• Adult
• Aged
• Aged, 80 and over
• Female
• Humans
• Male
• Middle Aged
• B7-H1 Antigen/metabolism
• B7-H1 Antigen/genetics
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• CD8-Positive T-Lymphocytes/metabolism
• CD8-Positive T-Lymphocytes/immunology
• China/epidemiology
• East Asian People/genetics
• Mutation
• Urinary Bladder Neoplasms/genetics
• Urinary Bladder Neoplasms/metabolism
• Urinary Bladder Neoplasms/pathology

• AstraZeneca, China

• PD-1/PD-L1 axis
• bladder carcinoma
• immune system
• immunotherapy

• Humans
• Urinary Bladder Neoplasms/metabolism
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/genetics
• B7-H1 Antigen/metabolism
• B7-H1 Antigen/genetics
• Prognosis
• Biomarkers, Tumor/metabolism
• Immunohistochemistry
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/pharmacology
• Immunotherapy/methods
• Programmed Cell Death 1 Receptor/metabolism
• Programmed Cell Death 1 Receptor/antagonists & inhibitors

• bladder tumor
• muscle invasive
• papillary
• pd-l1
• urothelial carcinoma

• Clinical significance
• Immune escape
• Lymph nodes
• PD-1
• T cells
• bladder cancer

• NMIBC
• PD-L1
• biomarker
• bladder cancer

• japanese population
• pd-1
• pd-l1
• polymorphism
• urothelial cell carcinoma

Schistosoma haematobium, the causative agent of urogenital schistosomiasis, is a carcinogen type 1 since 1994. It is strongly associated with bladder squamous-cell carcinoma in endemic regions, where it accounts for 53-69% of bladder-carcinoma cases. This histological subtype is associated with chronic inflammation being more aggressive and resistant to conventional chemo and radiotherapy. Immune-Checkpoint-Blockage (ICB) therapies targeting the Programmed-Cell-Death-Protein-1(PD-1)/Programmed-Cell-Death-Ligand-1(PD-L1) axis showed considerable success in treating advanced bladder urothelial carcinoma. PD-L1 is induced by inflammatory stimuli and expressed in immune and tumor cells. The binding of PD-L1 with PD-1 modulates immune response leading to T-cell exhaustion. PD-L1 presents in several isoforms and its expression is dynamic and can serve as a companion marker for patients’ eligibility, allowing the identification of positive tumors that are more likely to respond to ICB therapy. The high PD-L1 expression in bladder-urothelial-carcinoma and squamous-cell carcinoma may affect further ICB-therapy application and outcomes. In general, divergent histologies are ineligible for therapy. These treatments are expensive and prone to auto-immune side effects and resistance. Thus, biomarkers capable of predicting therapy response are needed. Also, the PD-L1 expression assessment still needs refinement. Studies focused on squamous cell differentiation associated with S. haematobium remain scarce. Furthermore, in low and middle-income-regions, where schistosomiasis is endemic, SCC biomarkers are needed. This mini-review provides an overview of the current literature regarding PD-L1 expression in bladder-squamous-cell-carcinoma and schistosomiasis. It aims to pinpoint future directions, controversies, challenges, and the importance of PD-L1 as a biomarker for diagnosis, disease aggressiveness, and ICB-therapy prognosis in bladder-schistosomal-squamous-cell carcinoma.

• Apoptosis
• B7-H1 Antigen/metabolism
• Carcinogens
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Transitional Cell/drug therapy
• Humans
• Ligands
• Programmed Cell Death 1 Receptor
• Urinary Bladder
• Urinary Bladder Neoplasms

• D43 TW010568 FIC NIH HHS
• Fogarty International Center

• PD-L1
• PLGA-PEG
• bladder cancer
• mesoporous silica nanoparticles
• miR-34a

PD-L1 and B7-H3 have been found to be overexpressed in urothelial carcinoma (UC) of the urinary bladder. Recent studies have also demonstrated that B7-H3 and PD-L1 can promote resistance to platinum-based drugs but the predictive value of B7-H3 expression in patients treated with platinum-based chemotherapy is unknown. This study aims to investigate the association of PD-L1 and B7-H3 tumor expression with oncological outcomes in patients who underwent radical cystectomy (RC) and received subsequent adjuvant chemotherapy.

Immunohistochemistry was performed on paraffin-embedded sections from bladder and lymph node specimens of 81 patients who had RC for bladder cancer. PD-L1 and B7-H3 expression on tumor cells was assessed by immunohistochemistry in both primary tumors and lymph node specimens. Association with clinicopathologic outcomes was determined using Fisher's exact test and postoperative survival using Kaplan–Meier survival curves and Cox regression model.

B7-H3 expression in cystectomy specimens was more common than PD-L1 expression (72.8% vs. 35.8%). For both markers, no association was found with pathologic tumor stage, lymph node (LN) status, and histological subtype. Similar findings were observed for double-positive tumors (PD-L1⁺B7-H3⁺). Concordance between the primary tumor and patient-matched lymph nodes was found in 76.2% and 54.1% of patients for PD-L1 and B7-H3, respectively. PD-L1 tumor expression was not associated with oncologic outcomes. However, B7-H3 expression was associated with recurrence-free survival (HR: 2.38, 95% CI 1.06–5.31, p = 0.035) and cancer-specific survival (HR: 2.67, 95% CI 1.18–6.04, p = 0.019).

In our single institutional study, B7-H3 is highly expressed in patients with UC treated with adjuvant chemotherapy and it was associated with decreased recurrence-free survival and cancer-specific survival. Pending further validation in larger cohorts, B7-H3 expression may function as a predictor of response to adjuvant chemotherapy and thus be useful in patient and regimen selection.

The online version contains supplementary material available at 10.1186/s12894-022-01044-1.

• Adjuvant chemotherapy
• B7-H3
• Bladder cancer
• Immunohistochemistry
• PD-L1

• bladder cancer
• macrophage-targeting immunotherapy
• macrophages

The aim of this study is to investigate the prognostic role of programmed death ligand-1 (PD-L1) on tumor-infiltrating immune cells (TIICs) in patients after radical cystectomy (RC) for bladder cancer (BCa).

We retrospectively reviewed 92 “high-risk” (≥pT3a and/or pN+) patients who underwent RC for BCa, without adjuvant chemotherapy (AC), between April 2014 and December 2019. PD-L1 on TIICs was measured only using the VENTANA (SP-142) immunohistochemistry assay. Patients were categorized into three groups based to the percentage of the tumor area covered by PD-L1 on TIICs: IC0 (<1%), IC1 (≥1% and <5%), and IC2/3 (≥5%). Positive PD-L1 was defined as IC2/3 (≥5%). Kaplan–Meier survival analysis was used to illustrate recurrence-free survival (RFS), and Cox proportional hazard models were used to identify predictive factors of tumor recurrence.

Within the cohort, the proportions of PD-L1 IC0, IC1, and IC2/3 were 21.7%, 23.9%, and 54.4%, respectively. At follow-up (mean 31.3 months), tumor recurrence was identified in 49 patients (53.3%). Using multivariable analysis, tumor stage (pT4; P=0.005), positive lymph nodes (P=0.021), and positive PD-L1 on TIICs (P=0.010) were independent predictors of tumor recurrence. The 2- and 3-year RFS rates were 67.7% and 64.2% in negative PD-L1 on TIICs, while 27.8% and 22.3% in positive PD-L1 on TIICs, respectively.

Positive PD-L1 on TIICs was significantly associated with poorer RFS in “high-risk” patients after RC without AC. Our results support the use of adjuvant immunotherapy in “high-risk” patients with positive PD-L1 on TIICs after RC.

• high-risk
• programmed death ligand-1
• radical cystectomy
• recurrence
• tumor-infiltrating immune cell

• Biomarker
• Bladder Cancer
• Immune Checkpoint Inhibitors
• Metastasis
• Programmed Death Ligand 1
• Urothelial Carcinoma

• PD-L1
• prognosis
• tumor cells
• tumor-infiltrating immune cells
• urothelial carcinoma

• bladder cancer
• chemotherapy
• immunotherapy
• resistance
• sPD-L1

In the present study, we analyzed Programmed Death Ligand-1 (PD-L1) expression in radical cystectomy (RC) specimens from patients with muscle-invasive urothelial carcinoma (UC), in order to assess any correlations with specific clinicopathological features and its potential prognostic value. A multi-institutional study was performed within the departments of urology and pathology at the Mureș County Hospital, Romania, and Centre Hospitalier Lyon Sud, France. Sixty-nine patients with MIBC were included, for whom tumor histology (conventional versus histological variant/differentiation), tumor extension (T), lymph node involvement (N), and distant metastases (M) were recorded. PD-L1 immunostaining was performed using the 22C3 clone and was interpreted using the combined positive score (CPS) as recommended (Dako Agilent, Santa Clara, CA, USA). Positive PD-L1 immunostaining was more prevalent among UCs with squamous differentiation compared to conventional UCs and trended towards an improved OS (p = 0.366). We found the T stage to be a risk factor for poor survival in PD-L1-positive patients (HR 2.9, p = 0.021), along with the N stage in PD-L1-negative patients (HR 1.98, p = 0.007). No other clinicopathological factor was found to be significantly associated with PD-L1 positivity. Thus, we confirm the need for PD-L1 immunostaining prior to initiating immune checkpoint inhibitor therapy for a more accurate assessment of the patients’ chances of responding to treatment.

• immune checkpoint inhibitors
• lymphatic node status overall survival
• muscle-invasive bladder cancer
• tumor stage

Introduction: Small cell carcinoma of the urinary tract (SCCUT) is a rare finding with poor clinical course. This study sheds light on the molecular subtype and identifies risk factors in patients diagnosed with SCCUT.

Methods: Immunohistochemical expression of immunotherapy target programmed death ligand 1 (PD-L1) and luminal (GATA3), basal (p63), and p53 markers are assessed in patients diagnosed with SCCUT. Univariate analysis identified risk factors. Overall survival (OS) is computed using the Kaplan–Meier method.

Results: Tissue was available for 70.2% (33/47). All showed a high PD-L1 expression phenotype. p53 is seen in 93.9% (31/33), mostly as overexpression, GATA3 in 45.5% (15/33), and p63 in 57.6% (19/33). For the entire cohort (n = 47), 1-year survival was 59.6%, and the median OS was 17 months. Univariate analysis shows that chemotherapy [hazard ratio (HR) = 0.29, 95% confidence interval (CI) = 0.14–0.61, p = 0.001], radical surgery (HR = 0.37, 95% CI = 0.18–0.76, p = 0.007), and diagnosis of non-pure SCCUT (HR = 0.44, 95% CI = 0.22–0.86, p = 0.02) are favorable prognostic features. Metastasis had negative associations with survival (HR = 2.1, 95% CI = 1.1–4.2, p = 0.03).

Conclusions: In this series, pure and mixed SCCUT are characterized by p53 overexpression and a high PD-L1 phenotype. Histology of non-pure SCCUT is a positive prognosticator, and radical cystectomy or chemotherapy can improve OS. These findings demonstrate that SCCUT may be eligible for PD-L1 immunotherapy.

• PD-L1
• bladder
• p53
• risk factors
• small cell carcinoma
• survival

• Combined positive score
• Immune checkpoint inhibitor
• Programmed death-ligand 1
• Survival
• Upper tract urothelial carcinoma

• Cellular therapy
• Checkpoint inhibitors
• Cytokines
• Immunotherapy
• Prostate cancer
• Renal cell carcinoma
• Urothelial carcinoma
• Vaccines

• Carcinoma, Renal Cell/therapy
• Carcinoma, Transitional Cell
• Humans
• Immunotherapy
• Kidney Neoplasms/therapy
• Male
• Urinary Bladder Neoplasms

• P30 CA016672 NCI NIH HHS

• Immune checkpoint therapy
• Microsatellite instability
• PD-1
• PD-L1
• Tumour mutational burden
• Tumour-infiltrating lymphocyte

• Antineoplastic Agents, Immunological/administration & dosage
• Antineoplastic Agents, Immunological/adverse effects
• Antineoplastic Agents, Immunological/therapeutic use
• Biomarkers, Tumor
• Disease Susceptibility
• Genetic Predisposition to Disease
• Humans
• Immune Checkpoint Inhibitors/administration & dosage
• Immune Checkpoint Inhibitors/adverse effects
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Proteins/genetics
• Immune Checkpoint Proteins/metabolism
• Immunotherapy
• Lymphocytes, Tumor-Infiltrating/drug effects
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms/drug therapy
• Neoplasms/etiology
• Neoplasms/mortality
• Neoplasms/pathology
• Prognosis
• Treatment Outcome

• Anti-angiogenic agents
• Biomarkers
• Combination therapy
• Immune checkpoint inhibitors
• Targeted therapy
• Urothelial carcinoma

Upper tract urothelial carcinoma (UTUC) is a very uncommon disease that occupies for <5% of all urothelial cancers. Radical nephroureterectomy (RNU) remains the standard-of-care for UTUC; however, when patients with locally advanced UTUC are treated with RNU only, the recurrence rate is high. Therefore, perioperative chemotherapy has been proposed given the high systemic recurrence rate. Moreover, there is growing evidence that neoadjuvant chemotherapy (NAC) plays an important role in the treatment of UTUC. Several studies and meta-analyses have reported the beneficial effect of NAC on survival outcomes and pathologic downstaging of patients with UTUC. However, the recommendation of NAC for UTUC is primarily based on level 1 evidence that demonstrated a beneficial effect on survival outcomes in patients with bladder cancer. The chemotherapy regimen for patients with UTUC is also based on that used for patients with bladder cancer. Nevertheless, the use of NAC for UTUC has some limitations, including the possibility of overtreatment. Therefore, selection criteria for NAC are needed, as are further trials to identify the most suitable patients and validate its use in daily clinical practice.

• Chemotherapy
• Neoadjuvant
• Nephroureterectomy
• Upper tract urothelial carcinoma (UTUC)

Background: Several studies investigating the role of PD-L1 in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU) to predict prognosis had been published and great controversy existed among them. We, therefore, in the meta-analysis, reported the association between PD-L1 and survival in UTUC patients who underwent RNU.

Methods: We searched the PubMed, Cochrane Library, EMBASE, and Web of Science by April 1, 2020. Hazard ratio (HR) and odds ratio (OR) were adopted to evaluate relationships between PD-L1 and survival outcomes, and tumor features, respectively. We formulated clinical questions and organized following the PICOS strategy.

Results: Eight retrospective studies incorporating 1406 patients were included. The pooled positive rate of PD-L1 in UTUC patients was 21.0% (95% CI = 13.0–30.0%, I² = 95.3%). Furthermore, higher PD-L1 in tumor tissues was related to shorter cancer-specific survival (CSS) in radically resected UTUC patients (HR = 1.63, 95% CI = 1.17–2.26, I² = 0.0%), but was not associated with overall survival (OS) (HR = 1.49, 95% CI = 0.76–2.91, I² = 74.9%). Subgroup analyses indicated associations between higher PD-L1 and shorter CSS in both Caucasus (HR = 1.72, 95% CI = 1.02–2.92, I² = 0.0%) and Asian (HR = 1.57, 95% CI = 1.03–2.39, I² = 23.1%) UTUC patients. Furthermore, PD-L1 was related to tumor grade of UTUC (High vs. Low, OR = 3.56, 95% CI = 1.82–6.97, P = 0.000) and invasive depth (pT3+pT4+pT2 vs. pT1+pTa/pTis, OR = 2.53, 95% CI = 1.07–5.96, P = 0.001). In the cumulative meta-analysis, results indicated that the 95% CIs narrowed as the pooled results gradually moved near the null.

Conclusions: PD-L1 overexpression was related to worse survival outcomes in UTUC patients after RNU. It may be useful to incorporate PD-L1 into prognostic tools to select appropriate treatment strategies for UTUC. PD-L1 can also be clinically used for survival anticipation, risk stratification, and patient counseling. However, the pooled findings should be considered tentative until ascertained by more researches.

• PD-L1
• immune checkpoint
• meta-analysis
• prognostic biomarker
• upper tract urothelial carcinoma (UTUC)

c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). The HGF/c-Met system is important for malignant aggressiveness in various types of cancer, including bladder cancer (BC). However, although phosphorylation is the essential step required for biological activation of c-Met, pathological roles of phosphorylated c-Met at the clinical and molecular levels in patients with BC are not fully understood. In the present study, the expression levels of c-Met and the phosphorylation of two of its tyrosine residues (pY1234/pY1235 and pY1349) were immunohistochemically examined in 185 BC tissues. The associations between these expression levels and cancer cell invasion, metastasis, and cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), VEGF-A and programmed death ligand 1 (PD-L1) levels were investigated. c-Met was associated with muscle invasion (P=0.021), as well as the expression levels of HO-1 (P=0.028) and PD-L1 (P<0.001), whereas pY1349 c-Met was associated with muscle invasion (P=0.003), metastasis (P=0.025), and COX-2 (P=0.017), HO-1 (P=0.031) and PD-L1 (P=0.001) expression. By contrast, pY1234/1235 c-Met was associated with muscle invasion and metastasis (P=0.006 and P=0.012, respectively), but not with the panel of cancer-associated molecules. Furthermore, COX-2 and PD-L1 expression were associated with muscle invasion and metastasis, respectively (P=0.045 and P=0.036, respectively). Hence, c-Met serves important roles in muscle invasion by regulating HO-1 and PD-L1, whereas its phosphorylation at Y1349 is associated with muscle invasion and metastasis via the regulation of COX-2, HO-1 and PD-L1 in patients with BC. Furthermore, phosphorylation at Y1234/1235 may lead to muscle invasion and metastasis via alternate mechanisms associated with c-Met and pY1349 c-Met.

• bladder cancer
• c-Met
• cyclooxygenase-2
• heme oxygenase-1
• phosphorylation
• programmed death ligand 1
• vascular endothelial growth factor-A

• PD-L1 expression
• immune cells
• malignant cells
• molecular subtype
• non-muscular invasive bladder cancer
• relapse
• survival
• tumor grade

• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Adenocarcinoma/virology
• Biomarkers, Tumor/genetics
• Carcinoma, Basal Cell/genetics
• Carcinoma, Basal Cell/pathology
• Carcinoma, Basal Cell/virology
• Carcinoma, Transitional Cell/genetics
• Carcinoma, Transitional Cell/pathology
• Carcinoma, Transitional Cell/virology
• Epstein-Barr Virus Infections/complications
• Epstein-Barr Virus Infections/virology
• Gene Expression Profiling
• Herpesvirus 4, Human/isolation & purification
• High-Throughput Nucleotide Sequencing
• Humans
• Tumor Cells, Cultured
• Urinary Bladder Neoplasms/genetics
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/virology

• P30 CA016086 NCI NIH HHS
• P30 ES010126 NIEHS NIH HHS
• U54 CA156733 NCI NIH HHS

• Biomarker
• HPV
• Immunohistochemistry
• Immunotherapy
• Penile cancer

During the last decade, the dynamics of the cellular crosstalk have highlighted the significance of the host vs. tumor interaction. This resulted in the development of novel immunotherapeutic strategies in order to modulate/inhibit the mechanisms leading to escape of tumor cells from immune surveillance. Different monoclonal antibodies directed against immune checkpoints, e.g., the T lymphocyte antigen 4 and the programmed cell death protein 1/ programmed cell death ligand 1 have been successfully implemented for the treatment of cancer. Despite their broad activity in many solid and hematologic tumor types, only 20–40% of patients demonstrated a durable treatment response. This might be due to an impaired T cell tumor interaction mediated by immune escape mechanisms of tumor and immune cells as well as alterations in the composition of the tumor microenvironment, peripheral blood, and microbiome. These different factors dynamically regulate different steps of the cancer immune process thereby negatively interfering with the T cell –mediated anti-tumoral immune responses. Therefore, this review will summarize the current knowledge of the different players involved in inhibiting tumor immunogenicity and mounting resistance to checkpoint inhibitors with focus on the role of tumor T cell interaction. A better insight of this process might lead to the development of strategies to revert these inhibitory processes and represent the rational for the design of novel immunotherapies and combinations in order to improve their efficacy.

• T cells
• checkpoint inhibitors
• inflammation
• microbiome
• tumor growth
• tumor microenvironment

In patients with muscle invasive bladder cancer (MIBC), neoadjuvant chemotherapy (NAC) prior to radical cystectomy has improved survival but there is an urgent unmet need to identify prognostic and predictive biomarkers to stratify patients who will benefit from treatment. This study aimed to examine the composition of tumor-infiltrating immune cells in MIBC, with particular reference to the clinical outcome and the potential modifying effect of NAC. To this end, the expression of CD8⁺ and FoxP3⁺ T cells, CD20⁺ B cells, PD-1⁺ and PD-L1⁺ immune cells and PD-L1⁺ tumor cells was evaluated by immunohistochemistry on tissue microarrays with paired transurethral resection (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients, 65 of whom had received NAC. Kaplan–Meier and Cox regression analyses were applied to assess the impact of investigated cell subsets on time to recurrence (TTR). In cystectomy specimens, high infiltration of the investigated immune cell populations, but not PD-L1⁺ tumor cells, were independently associated with a prolonged TTR, whereas in TURB specimens, this association was only seen for CD8⁺ lymphocytes. An additive beneficial prognostic effect of NAC was seen for the majority of the cell subsets but there was no significant interaction between any immune marker and NAC in relation to TTR. Furthermore, no differences in cell densities prior to NAC treatment were observed between complete and non-complete responders, or pre- and posttreatment in non-complete responders. In conclusion, immune cell infiltration provides important prognostic information in both pre- and postsurgical samples of MIBC, independently of NAC.

• Bladder cancer
• immunotherapy
• neoadjuvant chemotherapy
• prognosis
• tumor microenvironment

Objective: Our objective was to conduct a meta-analysis to investigate the clinicopathological features and prognostic value of programmed cell death ligand 1 (PD-L1) expression in patients with urothelial carcinoma (UC).

Materials and methods: Twenty-seven studies with 4,032 patients were included in the meta-analysis. Pooled ORs and 95% CIs were used to examine the associations between clinical factors and PD-L1 expression. HRs and 95% CIs were extracted from eligible studies. Heterogeneity was evaluated using the chi-squared-based Q test and I² statistic.

Results: Expression of PD-L1 on tumor cells (TCs) was associated with muscle-invasive disease (OR=3.67, 95% CI: 2.53–5.33), and inversely associated with the history of intravesical bacilli Calmette-Guerin therapy (OR=0.39, 95% CI: 0.18–0.82) in bladder cancer patients. PD-L1 expression on TCs was associated with worse overall survival (HR=2.06, 95% CI: 1.38–3.06) in patients with organ-confined bladder cancer. PD-L1 expression in patients with UC was significantly related to better objective response rate after PD-1/PD-L1 antibody treatment.

Conclusions: Expression of PD-L1 on TCs was associated with muscle-invasive disease in patients with bladder cancer. Patients with PD-L1-positive UC had a significantly better response to PD-1/PD-L1 targeted treatment.

• immunotherapy
• meta-analysis
• prognosis
• programmed cell death ligand 1
• urothelial carcinoma

• Bladder cancer
• Checkpoint inhibitors
• Immunotherapy
• PD-1
• Urothelial carcinoma

• BCG
• Immune checkpoints
• Immune phenotype
• Non-muscle invasive bladder cancer
• Peripheral blood mononuclear cells
• Predictive factors

• Aged
• BCG Vaccine/therapeutic use
• Carcinoma, Transitional Cell/mortality
• Carcinoma, Transitional Cell/pathology
• Carcinoma, Transitional Cell/therapy
• Chi-Square Distribution
• Cohort Studies
• Disease-Free Survival
• Female
• Humans
• Immunotherapy/methods
• Leukocytes, Mononuclear/immunology
• Male
• Middle Aged
• Neoplasm Invasiveness/pathology
• Neoplasm Staging
• Phenotype
• Prospective Studies
• Statistics, Nonparametric
• Survival Analysis
• Urinary Bladder Neoplasms/mortality
• Urinary Bladder Neoplasms/pathology
• Urinary Bladder Neoplasms/therapy

• R01 CA201189 NCI NIH HHS
• T32 AI007605 NIAID NIH HHS
• T32 AI007647 NIAID NIH HHS

Metastatic urothelial cancer is an aggressive disease associated with a poor prognosis. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly occurs. After failure of platinum-based therapy and in cisplatin-ineligible patients, therapeutic options are limited. Malignant cells evolve mechanisms to evade immune recognition, including the expression of cell-surface molecules, named immune checkpoints, on tumor and tumor-specific lymphocytes. Immunotherapy, by targeting these checkpoints, represents a new tool to improve the patient outcome in advanced urothelial carcinoma (UC). Recently, the US FDA approved, in a short time, several immune checkpoint inhibitors in metastatic UC, both after failure of platinum-based therapy and in first-line setting in cisplatin-ineligible patients. This article aims to review the place of immunotherapy in advanced UC.

Urothelial carcinoma is an aggressive disease and therapeutic options are limited in patients with advanced stage who are refractory to chemotherapy. Immunotherapy represents a milestone for these patients; different immune checkpoint inhibitors have shown significant activity in advanced urothelial carcinoma and are currently available both in the second-line metastatic setting (after failure of platinum-based therapy) and in the first-line setting in cisplatin-ineligible patients. Furthermore, these agents are better tolerated than chemotherapy. PD-L1 expression is not an ideal biomarker and further research is evaluating innovative methods to facilitate selection of patients who are most likely to benefit from these agents.

• atezolizumab
• avelumab
• durvalumab
• gene signature
• immune checkpoint inhibitors
• immunotherapy
• nivolumab
• pembrolizumab
• programmed death ligand-1 (PD-L1)
• urothelial carcinoma