870 Investigating sexual dimorphism in the tumor immune microenvironment of non-muscle invasive bladder cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A922-A922
Author(s):  
Stephen Chenard ◽  
Chelsea Jackson ◽  
Thiago Vidotto ◽  
Celine Hardy ◽  
Tamara Jamaspishvilli ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Sexual Dimorphism ◽  
B Cell ◽  
Invasive Bladder Cancer ◽  
High Grade ◽  
Immune Microenvironment ◽  
Muscle Invasive Bladder Cancer ◽  
Female Patients ◽  
Tumor Immune Microenvironment ◽  
Muscle Invasive

BackgroundWhile the incidence of non-muscle invasive bladder cancer (NMIBC) is four times higher in men than women, female patients display earlier recurrence than their male counterparts following treatment with Bacillus Calmette-Guerin (BCG) immunotherapy.1 While patient sex (biological differences) and gender (social/behavioral differences) have long been associated with NMIBC incidence and clinical outcome, these factors remain the most understudied phenotypes in biomarker and treatment design.2 We hypothesized that sexual dimorphism in the pre-existing tumor immune microenvironment (TIME) may contribute to the poor clinical outcomes observed in female NMIBC patients.MethodsTo test this hypothesis, we interrogated the expression patterns of genes associated with specific immune cell populations and immune checkpoint pathways using tumor transcriptome profiles from n=460 NMIBC patients (357 males and 103 females). Based on this interrogation, we utilized multiplex immunofluorescence to selectively evaluate the density and spatial distribution of CD79a+ (B), CD163+ (M2-like tumor associated macrophages), and PD-L1+ (programmed death ligand 1) cells in an independent cohort of 510 NMIBC tumors collected from n=390 patients (305 males and 85 females).ResultsWe observed significantly higher expression of immune checkpoints genes CTLA4, PDCD1, TIGIT, LAG3 and ICOS in tumors from female patients. Importantly, transcript levels of the B cell recruiting chemokine CXCL13 and the B cell surface molecule CD40 were significantly increased in tumors from female patients. Multiplex immunofluorescence revealed that CD163+ cells were significantly higher in epithelial and stromal compartments of high-grade tumors (p = 0.0011, p = 0.00034, respectively) from female patients compared to males. While no sex-associated differences were observed in the density of CD79a+ B cells, this population was found to be significantly increased in the epithelial and stromal compartments (p = 6.9e-9, 9.4e-10, respectively) of high-grade tumors compared to low-grade tumors. PD-L1 expression was significantly higher in the epithelial compartment of high-grade tumors from female patients (p = 0.04). Kaplan-Meier survival analysis showed that higher density of CD163+ and CD79a+ cells were independently associated with shorter recurrence free survival (RFS). Notably, these differences in RFS remained in BCG immunotherapy-naïve patients (n=170).ConclusionsThese findings are the first evidence of sexual dimorphism in the TIME of NMIBC and may help to partially explain the worse clinical outcomes experienced by female patients. This study also provides the first evidence of the negative prognostic impact of B cells in NMIBC. Overall, this study provides insight into more rational implementation of immune-based therapies in female NMIBC patients.Ethics ApprovalThis study was approved by the Ethics Review Board at Queen’s University, Kingston, ON, Canada.ReferencesSaginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of bladder cancer. Med Sci 2020;8.Uhlig A, Strauss A, Seif Amir Hosseini A, Lotz J, Trojan L, Schmid M, et al. Gender-specific differences in recurrence of non-muscle-invasive bladder cancer: a systematic review and meta-analysis. Eur Urol Focus 2018;4:924–36.

scholarly journals Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

2021 ◽  
Author(s):  
Stephen Chenard ◽  
Chelsea Jackson ◽  
Thiago Vidotto ◽  
Lina Chen ◽  
Céline Hardy ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Sexual Dimorphism ◽  
B Cells ◽  
Immune Checkpoint ◽  
Cell Types ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Female Patients ◽  
Muscle Invasive

AbstractNon-muscle invasive bladder cancer (NMIBC) is significantly more common in men than women. However, female patients with NMIBC often present with more aggressive disease and do not respond as well to immunotherapy treatments. We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients. To test this hypothesis, we interrogated the expression patterns of genes associated with specific immune cell types and immune regulatory pathways using tumor whole transcriptome profiles from male (n=357) and female (n=103) patients with NMIBC. High-grade tumors from female patients exhibited significantly increased expression of CD40, CTLA4, PDCD1, LAG3 and ICOS immune checkpoint genes. Based on the significant differences in expression profiles of these genes and the cell types that most commonly express these in the TIME, we evaluated the density and spatial distribution of CD8+Ki67+ (activated cytotoxic T cells), FoxP3+ (regulatory T cells), CD103+ (tissue resident T cells), CD163+ (M2-like tumor associated macrophages), CD79a+ (B cells), PD-L1+ (Programmed-Death Ligand-1) and PD-1+ cells using multiplexed immunofluorescence in an independent cohort of 332 patient tumors on a tissue microarray (n=259 males and n=73 females). Tumors from female patients showed significantly higher infiltration of CD163+ macrophages and PD-L1+ cells compared to tumors from male patients. Notably, increased infiltration of CD163+ macrophages and CD79a+ B cells independently associated with decreased recurrence free survival. Not only do these results have the potential to inform the rational utilization of immunomodulatory therapies based on the TIME of both male and female patients with NMIBC, these novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials.

Evaluating Patient-Defined Priorities for Female Patients with Bladder Cancer

2020 ◽  
pp. 1-8
Author(s):  
Amanda X. Vo ◽  
Mary Kate Keeter ◽  
Emily S. Tuchman ◽  
Joshua J. Meeks ◽  
Alicia K. Morgans
Keyword(s):  
Bladder Cancer ◽  
Locally Advanced ◽  
Invasive Bladder Cancer ◽  
Emotional Wellbeing ◽  
Structured Interviews ◽  
Muscle Invasive Bladder Cancer ◽  
Care Experience ◽  
Female Patients ◽  
Muscle Invasive ◽  
Optimal Approach

BACKGROUND: Although bladder cancer is much more common in men than in women, female patients with bladder cancer present with more locally advanced tumors and have worse disease-specific outcomes than male patients, even after controlling for biological differences. There is a paucity of research regarding the optimal approach to caring for female patients with bladder cancer in ways that maximize patient satisfaction, preferences, and values. OBJECTIVE: We sought to explore patient-defined priorities and areas in need of improvement for female patients with bladder cancer from the patient perspective. METHODS: We conducted focus group sessions and semi-structured interviews of women treated for bladder cancer to identify patient priorities and concerns until reaching topic saturation. Transcripts were analyzed thematically. RESULTS: Eight patients with muscle-invasive bladder cancer and six patients with non-muscle-invasive bladder cancer participated in two focus groups and seven interviews total. Three themes emerged as significantly affecting the care experience: physical impacts, mental health and emotional wellbeing, and the patient-provider interaction. Each theme included patient-defined specific recommendations on approaches to optimizing the care experience for women with bladder cancer. CONCLUSIONS: Although most participants were satisfied with the quality of care they received, they identified several opportunities for improvement. These concerns centered around enhancing support for patients’ physical and mental needs and strengthening the patient-provider interaction. Efforts to address these needs and reduce gender disparate outcomes via quality improvement initiatives are ongoing.

scholarly journals Effectivity of intravescical thermo-chemotherapy prophylaxis for patients with high recurrence and progression risk for non-muscle invasive bladder cancer

2017 ◽  
Vol 89 (2) ◽  
pp. 102 ◽  
Author(s):  
Ali Serdar Gözen ◽  
Paolo Umari ◽  
Walter Scheitlin ◽  
Fuat Ernis Su ◽  
Yigit Akin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Recurrent Disease ◽  
Bladder Wall ◽  
Invasive Bladder Cancer ◽  
Outpatient Basis ◽  
High Grade ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Background&Aim: High grade non-muscle invasive bladder cancer (NMIBC) is common in urological practice. Most of these cancers are or become refractory to intravesical immunotherapy and chemotherapy. Here we evaluated the efficacy of combined local bladder hyperthermia and intravesical mitomycin-C (MMC) instillation in patients with high-risk recurrent NMIBC. Materials and methods: Between February 2014 and December 2015, 18 patients with high risk NMIBC were enrolled. Patients were treated in an outpatient basis with 6 weekly induction sessions followed by monthly maintenance sessions with intravesical MMC in local hyperthermia with bladder wall thermo-chemotherapy (BWT) system (PelvixTT system, Elmedical Ltd., Hod Hasharon, Israel). The follow-up regimen included cystoscopy after the induction cycle and thereafter with regular intervals. Time to disease recurrence was defined as time from the first intravesical treatment to endoscopic or histological documentation of a new bladder tumour. Adverse events were recorded according to CTC 4.0 (Common Toxicity Criteria) score system. Results: Mean age was 72 (32-87) years. 10 patients had multifocal disease, 9 had CIS, 6 had recurrent disease and 2 had highly recurrent disease (> 3 recurrences in a 24 months period). 6 patients underwent previous intravesical chemotherapy with MMC. The average number of maintenance sessions per patient was 7.6. After a mean follow-up of 433 days, 15 patients (83.3%) were recurrence-free. 3 patients had tumour recurrence after a mean period of 248 days without progression. Side effects were limited to grade 1 in 2 patients and grade 2 in 1 patient. Conclusions: BWT seems to be feasible and safe in high grade NMIBC. More studies are needed to identify the subgroup of patients who may benefit more from this treatment.

scholarly journals Does the Urinary Mast Cell Mediators Predict the Immune Response to BCG in Patients with Primary High-Grade Non-Muscle Invasive Bladder Cancer?

2020 ◽  
Author(s):  
Muhammed Fatih Simsekoglu ◽  
İslim Kaleler ◽  
Bulent Onal ◽  
Cetin Demirdag ◽  
Sinharib Citgez ◽  
...  
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Mast Cell ◽  
Critical Role ◽  
Invasive Bladder Cancer ◽  
High Grade ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive ◽  
Healthy Participants ◽  
Bcg Instillation

Background: Mast cells play a critical role in tumor-associated immune pathways. We aimed to determine whether the urinary mast cell mediators predict the immune response in patients with non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) immunotherapy. Methods: Nineteen patients who have received immunotherapy due to NMIBC and 19 healthy participants were enrolled. Urine samples were collected to assay N-methylhistamine, histamine, and tryptase levels immediately before the first BCG instillation, immediately after the third and sixth instillations, and four weeks after the sixth instillation in patients with NMIBC and at a single visit in healthy participants. Cystoscopic examinations were performed on the patient with NMIBC at three-month intervals for two years. The changes in urinary markers due to BCC response, BCG instillation, and the presence of NMIBC were assessed. Results: The average age was 56.1 ± 10.5 years in patients with NMIBC. Fourteen patients had high-grade Ta tumors, and 5 had high-grade T1 tumors. While 12 patients responded, 6 presented with recurrence and 1 with progression. There was no correlation between the levels of mast cell mediators and BCG response. The N-methylhistamine and histamine levels were increased significantly with the onset of immunotherapy, and N-methylhistamine levels were significantly decreased when immunotherapy was terminated. Pre-BCG estimated marginal means of N-methylhistamine were significantly higher in patients with NMIBC than healthy participants. Conclusions: Our study is the first study to identify the changes in mast cell mediators with the onset of immunotherapy and with the presence of bladder cancer. However, these mediators were not found to predict the patients’ response to immunotherapy.

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