Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint
Background: Non–muscle-invasive bladder cancer (NMIBC) is over three times as common in men as it is in women; however, female patients do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. Based on the established sexual dimorphi...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | European Urology Open Science |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666168321000938 |
| _version_ | 1819000799666110464 |
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| author | Stephen Chenard Chelsea Jackson Thiago Vidotto Lina Chen Céline Hardy Tamara Jamaspishvilli David Berman D. Robert Siemens Madhuri Koti |
| author_facet | Stephen Chenard Chelsea Jackson Thiago Vidotto Lina Chen Céline Hardy Tamara Jamaspishvilli David Berman D. Robert Siemens Madhuri Koti |
| author_sort | Stephen Chenard |
| collection | DOAJ |
| description | Background: Non–muscle-invasive bladder cancer (NMIBC) is over three times as common in men as it is in women; however, female patients do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. Based on the established sexual dimorphism in mucosal immune responses, we hypothesized that the tumor immune microenvironment of bladder cancer differs between the sexes, and this may contribute to discrepancies in clinical outcomes. Objective: To determine biological sex-associated differences in the expression of immune regulatory genes and spatial organization of immune cells in tumors from NMIBC patients. Design, setting, and participants: Immune regulatory gene expression levels in tumors from male (n = 357) and female (n = 103) patients were measured using whole transcriptome profiles of tumors from the UROMOL cohort. Multiplexe immunofluorescence was performed to evaluate the density and spatial distribution of immune cells and immune checkpoints in tumors from an independent cohort of patients with NMIBC (n = 259 males and n = 73 females). Outcome measurements and statistical analysis: Transcriptome sequencing data were analyzed using DESeq2 in R v4.0.1, followed by application of the Kruskal-Wallis test to determine gene expression differences between tumors from males and females. Immunofluorescence data analyses were conducted using R version 3.5.3. Survival analysis was performed using survminer packages. Results and limitations: High-grade tumors from female patients exhibited significantly increased expression of B-cell recruitment (CXCL13) and function (CD40)-associated genes and the immune checkpoint genes CTLA4, PDCD1, LAG3, and ICOS. Tumors from female patients showed significantly higher infiltration of PD-L1+ cells and CD163+ M2-like macrophages than tumors from male patients. Increased abundance of CD163+ macrophages and CD79a+ B cells were associated with decreased recurrence-free survival. Conclusions: These novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials in NMIBC. Patient summary: In this study, we measured the abundance of various immune cell types between tumors from male and female patients with non–muscle-invasive bladder cancer. We demonstrate that tumors from female patients have a significantly higher abundance of immunosuppressive macrophages that express CD163. Higher abundance of tumor-associated CD163-expressing macrophages and B cells is associated with shorter recurrence-free survival in both male and female patients. |
| first_indexed | 2024-12-20T22:39:04Z |
| format | Article |
| id | doaj.art-31b2fe73861147d59dae5341d87eb14a |
| institution | Directory Open Access Journal |
| issn | 2666-1683 |
| language | English |
| last_indexed | 2024-12-20T22:39:04Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Urology Open Science |
| spelling | doaj.art-31b2fe73861147d59dae5341d87eb14a2022-12-21T19:24:31ZengElsevierEuropean Urology Open Science2666-16832021-07-01295058Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune CheckpointStephen Chenard0Chelsea Jackson1Thiago Vidotto2Lina Chen3Céline Hardy4Tamara Jamaspishvilli5David Berman6D. Robert Siemens7Madhuri Koti8Queen’s Cancer Research Institute, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, CanadaQueen’s Cancer Research Institute, Kingston, ON, Canada; Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaDepartment of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USADepartment of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaQueen’s Cancer Research Institute, Kingston, ON, Canada; Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaQueen’s Cancer Research Institute, Kingston, ON, Canada; Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaQueen’s Cancer Research Institute, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada; Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaQueen’s Cancer Research Institute, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada; Department of Urology, Queen’s University, Kingston, ON, CanadaQueen’s Cancer Research Institute, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada; Department of Urology, Queen’s University, Kingston, ON, Canada; Corresponding author. Department of Biomedical and Molecular Sciences and Obstetrics and Gynecology, Queen’s University, Kingston, Ontario K7L3N6, Canada. Tel. +1 613 533 2979.Background: Non–muscle-invasive bladder cancer (NMIBC) is over three times as common in men as it is in women; however, female patients do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. Based on the established sexual dimorphism in mucosal immune responses, we hypothesized that the tumor immune microenvironment of bladder cancer differs between the sexes, and this may contribute to discrepancies in clinical outcomes. Objective: To determine biological sex-associated differences in the expression of immune regulatory genes and spatial organization of immune cells in tumors from NMIBC patients. Design, setting, and participants: Immune regulatory gene expression levels in tumors from male (n = 357) and female (n = 103) patients were measured using whole transcriptome profiles of tumors from the UROMOL cohort. Multiplexe immunofluorescence was performed to evaluate the density and spatial distribution of immune cells and immune checkpoints in tumors from an independent cohort of patients with NMIBC (n = 259 males and n = 73 females). Outcome measurements and statistical analysis: Transcriptome sequencing data were analyzed using DESeq2 in R v4.0.1, followed by application of the Kruskal-Wallis test to determine gene expression differences between tumors from males and females. Immunofluorescence data analyses were conducted using R version 3.5.3. Survival analysis was performed using survminer packages. Results and limitations: High-grade tumors from female patients exhibited significantly increased expression of B-cell recruitment (CXCL13) and function (CD40)-associated genes and the immune checkpoint genes CTLA4, PDCD1, LAG3, and ICOS. Tumors from female patients showed significantly higher infiltration of PD-L1+ cells and CD163+ M2-like macrophages than tumors from male patients. Increased abundance of CD163+ macrophages and CD79a+ B cells were associated with decreased recurrence-free survival. Conclusions: These novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials in NMIBC. Patient summary: In this study, we measured the abundance of various immune cell types between tumors from male and female patients with non–muscle-invasive bladder cancer. We demonstrate that tumors from female patients have a significantly higher abundance of immunosuppressive macrophages that express CD163. Higher abundance of tumor-associated CD163-expressing macrophages and B cells is associated with shorter recurrence-free survival in both male and female patients.http://www.sciencedirect.com/science/article/pii/S2666168321000938Non–muscle-invasive bladder cancerSexual dimorphismTumor immune microenvironmentTumor-associated macrophagesB cells |
| spellingShingle | Stephen Chenard Chelsea Jackson Thiago Vidotto Lina Chen Céline Hardy Tamara Jamaspishvilli David Berman D. Robert Siemens Madhuri Koti Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint European Urology Open Science Non–muscle-invasive bladder cancer Sexual dimorphism Tumor immune microenvironment Tumor-associated macrophages B cells |
| title | Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint |
| title_full | Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint |
| title_fullStr | Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint |
| title_full_unstemmed | Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint |
| title_short | Sexual Dimorphism in Outcomes of Non–muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint |
| title_sort | sexual dimorphism in outcomes of non muscle invasive bladder cancer a role of cd163 macrophages b cells and pd l1 immune checkpoint |
| topic | Non–muscle-invasive bladder cancer Sexual dimorphism Tumor immune microenvironment Tumor-associated macrophages B cells |
| url | http://www.sciencedirect.com/science/article/pii/S2666168321000938 |
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