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Background: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. Methods: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. Results: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. Conclusions: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients. [ABSTRACT FROM AUTHOR]

Muscle‐invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune‐molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor‐β (TGF‐β) inhibition. This immune‐molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC. [ABSTRACT FROM AUTHOR]

Background: Though programmed cell death‐ligand 1 (PD‐L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology‐mediated end joining (MMEJ) pathway, DNA polymerase theta (POLQ) was overexpressed in various malignancies, whose expression might have an influence on genomic stability, therefore altering the sensitivity to chemotherapy and immunotherapy. Methods: A total of 1304 patients with muscle‐invasive bladder cancer (MIBC) from six independent cohorts were included in this study. The Zhongshan Hospital (ZSHS) cohort (n = 134), The Cancer Genome Atlas (TCGA) cohort (n = 391), and the Neo‐cohort (n = 148) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n = 234) and the UNC‐108 cohort (n = 89) were used for the assessment of immunotherapeutic response. In addition, the relationship between POLQ and the immune microenvironment was assessed, and GSE32894 (n = 308) was used only for the evaluation of the immune microenvironment. Results: We identified POLQhigh PD‐L1high patients could benefit more from immunotherapy and platinum‐based chemotherapy. Further analysis revealed that high POLQ expression was linked to chromosome instability and higher tumor mutational burden (TMB), which might elicit the production of neoantigens. Further, high POLQ expression was associated with an active tumor immune microenvironment with abundant infiltration of immune effector cells and molecules. Conclusions: The study demonstrated that high POLQ expression was correlated with chromosome instability and antitumor immune microenvironment in MIBC, and the combination of POLQ and PD‐L1 could be used as a superior companion biomarker for predicting the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

Chemotherapy and immunotherapy yield survival benefits for muscle‐invasive bladder cancer (MIBC) patients, in which tumor microenvironment has been found to exert crucial roles through tipping the balance between antitumor immunity and immune evasion. Our study aims to explore the clinical significance and therapeutic role of intratumoral interleukin‐9‐producing cells (IL‐9+ cells) in MIBC. Two hundred fifty‐nine MIBC patients from two independent clinic centers were utilized for retrospective analysis in the study. Sixty‐five fresh MIBC tumor tissues were used to evaluate the infiltration and function of immune cells via flow cytometry and ex vivo intervention experiments. Three hundred ninety‐one MIBC patients of The Cancer Genome Atlas were applied for bioinformatics analysis. It was found that patients with high IL‐9+ cells infiltration had worse overall survival and relapse‐free survival. pT2 patients with low IL‐9+ cells infiltration could benefit more from adjuvant chemotherapy (ACT). IL‐9+ cells infiltration was correlated with decreased expression of granzyme B from CD8+ T cells and natural killer (NK) cells and perforin from CD8+ T cells, while blockade of IL‐9 reactivated the antitumor capacity of both cells leading to tumor regression. Furthermore, IL‐9+ cells infiltration could be a biomarker for predicting anti‐PD‐1 efficacy. In conclusion, IL‐9+ cells infiltration could be applied as an independent prognosticator for clinical outcome and ACT/anti‐PD‐1 effectiveness. IL‐9+ cells infiltration diminished the cytotoxicity of CD8+ T cells and NK cells resulting in tumor immune evasion, and thus targeting IL‐9 could be a potential therapeutic strategy for MIBC. What's new? The presence of IL‐9 seems to promote tumor progression in certain cancers but not others. Here, the authors investigated the clinical significance of IL‐9‐producing cells against muscle‐invasive bladder cancer (MIBC). They found that greater infiltration of the tumor with IL‐9+ cells led to a worse prognosis and immunosuppression, as CD8+ cells and NK cells produced fewer cytotoxic molecules. On the other hand, blocking IL‐9 restored the anti‐tumor activity of both CD8+ T cells and NK cells. These results suggest that IL‐9 blockade could be a potential therapy for MIBC. [ABSTRACT FROM AUTHOR]

Bladder cancer is the ninth most frequent-diagnosed disease worldwide, bearing high morbidity and mortality rates. Studies have shown that a particular population of CXCR5+CD8+ T cells was associated with superior prognosis in various tumor types, and yet its role in muscle-invasive bladder cancer (MIBC) remains unclear. In this study, 662 MIBC patients from 3 cohorts (Zhongshan Hospital, n = 141; Shanghai Cancer Center, n = 108; The Cancer Genome Atlas, n = 403) were analyzed retrospectively. 11 fresh resected samples of MIBC were examined to characterize the phenotype of CXCR5+CD8+ T cells and 402 MIBC patients from TCGA were applied for bioinformatics analysis. It was explored that the abundance of intratumoral CXCR5+CD8+ T cells indicated superior overall survival and disease-free survival. Patients with a higher infiltration of CXCR5+CD8+ T cells in tumor tissue benefit more from adjuvant chemotherapy (ACT). Intratumoral CXCR5+CD8+ T cells displayed cytolytic and self-renewal features. Remarkably, CXCR5+CD8+ T cells were mainly presented in the basal and stromal-rich subtypes of MIBC and tumors with enriched CXCR5+CD8+ T cells showed limited FGFR3 signaling signature and activated immunotherapeutic and EGFR associated pathway. In conclusion, we identified an excellent prognosis and ACT sensitive subtype of MIBC with intratumoral CXCR5+CD8+ T cell abundance. Tumors with high density of CXCR5+CD8+ T cells possessed potential sensitivity to immunotherapy and EGFR-targeted therapy. CXCR5+CD8+ T cells provide a new potential biomarker as well as a therapeutic target in MIBC. [ABSTRACT FROM AUTHOR]

Our previous studies revealed tumor-infiltrating neutrophils (TINs) played dichotomous roles in different cancers, indicating diverse TINs subtypes might orchestrate anti-tumor immunity or immune evasion, respectively. This study aimed to investigate the clinical significance and immune characteristics of CCR5+TINs in muscle-invasive bladder cancer (MIBC). Two hundred and fifty-seven MIBC patients from two clinical centers and 95 fresh MIBC samples were included. CCR5+TINs were stained by immunohistochemistry, and the relationship between patients' clinic-pathological features and prognosis was evaluated, respectively. Immunohistochemistry and flow cytometry were applied to assess the immune features of CCR5+TINs and their correlations with other immune cells. In vitro study was conducted to estimate immune characteristics of CCR5+TINs and their predictive potential for pembrolizumab therapeutic response. In the two MIBC cohorts, we found that high CCR5+TINs infiltration could predict better overall survival (OS, P=.032, 0.039) and recurrence-free survival (RFS, P=.001, 0.006) and be associated with survival benefit from adjuvant chemotherapy (ACT, P<.001 for OS and P=.022 for RFS, respectively) in merely pT2N0 MIBC. Maraviroc could partly reduce IFN-γ secretion by CCR5+TINs (P<.001). CCR5+TINs correlated with higher expression of effector molecules within CD8+T cells. Notably, pembrolizumab treatment could only elevate the apoptosis status of tumor cells in the CCR5+TINs high subgroup (P <.001), other than CCR5+TINs low subgroup (P=.481). Our results indicate that CCR5+TINs could prime anti-tumor immune response through autonomous IFN-γ release, thus leading to favorable prognosis and superior therapeutic response to ACT and immunotherapy in MIBC. [ABSTRACT FROM AUTHOR]

The role of IL-17A+ cells remains controversial among various cancer types. This study aimed to investigate the effects of IL-17A+ cells on tumor immune contexture and clinical outcome in muscle-invasive bladder cancer (MIBC). In this study, we enrolled 141 patients from Zhongshan Hospital, 118 patients from Shanghai Cancer Center and 403 patients from TCGA cohort. In vitro studies were conducted in 32 freshly resected tumors. Survival analysis was conducted using Kaplan–Meier and Cox regression analysis. The results suggested that patients with high levels of IL-17A+ cells had prolonged overall survival and recurrence-free survival (HR = 0.268, P <.001; and HR = 0.433, P <.001). Moreover, these patients tended to be at lower risk of death and recurrence after adjuvant chemotherapy (P =.012 and P =.004). An increased number of IL-17A+ cells correlated with the infiltration of several anti-tumor immune cells into tumors. In addition, IL-17A+ cells had an influence on the recruitment, proliferation, and activation of CD8+ cells, and were positively associated with the expression of several anti-tumor effector cytokines. In conclusion, tumor-infiltrating IL17A+ cells were correlated with an elevated anti-tumor immunity in MIBC. Besides, high infiltration of IL17A+ cells can predict benefit from ACT for MIBC patients. [ABSTRACT FROM AUTHOR]

Purpose: CD19+ tumor-infiltrating B-cells (CD19+ TIB) play a crucial role in tumorigenesis, but their clinical relevance in muscle-invasive bladder cancer (MIBC) remains unknown. This study aimed to investigate the prognostic value of CD19+ TIB for post-surgery survival and adjuvant chemotherapy response in MIBC.Experimental design: We assessed TIB by immunohistochemical staining of CD19 in 246 MIBC patients from Zhongshan Hospital and Shanghai Cancer Center. We evaluated the survival benefit of platinum-based chemotherapy according to CD19+ TIB. The mechanism underlying CD19+ TIB antitumor immunity was explored through the Cancer Genome Atlas (TCGA) dataset analysis and an in vitro Ag presentation assay.Results: CD19+ TIB extensively infiltrated into the tumor stroma of MIBC. Adjuvant chemotherapy (ACT) led to a significantly increased benefit in the high CD19+ TIB MIBC patients (P = 0.003). In multivariate analysis, high CD19+ TIB MIBC patients had significantly longer OS with ACT in the discovery set (HR = 0.487, P = 0.038). TCGA gene expression analyses showed enrichment of adaptive immunity, T-cell-mediated immunity, and antigen-presentation signaling pathways in high CD19+ TIB MIBC patients. Moreover, CD19+ TIB co-localized with activated CD4+ TIT and expressed surface markers characteristic of antigen-presenting cells. Finally, an antigen-presentation assay demonstrated the antigen-presentation function of CD19+ TIB.Conclusion: CD19+ TIB was identified as an independent prognostic factor, which could predict for post-surgery survival and platinum-based ACT benefits in MIBC. CD19+ TIB serve as antigen-presenting cells (APCs) to activate CD4+ TIT in the tumor environment of MIBC. [ABSTRACT FROM AUTHOR]

B7-H4, a sibling to PD-L1 in B7 family, has been reported to be a novel immune checkpoint that is prevalent among non-inflamed tumors. Herein, we attempt to explore the potential of B7-H4 in survival prediction and therapeutic guidance in muscle-invasive bladder cancer (MIBC) patients. This study included 391 patients from The Cancer Genome Atlas (TCGA) database and 122 patients from Zhongshan (ZS) Hospital. The evaluation of response to PD-L1 inhibitors was based on 270 patients in IMvigor210 cohort. Kaplan–Meier survival and multivariate analyses were performed to assess clinical outcomes in three cohorts. The correlation of B7-H4 expression with immune contexture and genomic alterations was analyzed based on immunohistochemistry, Microenvironment Cell Populations-counter (MCP-counter) tool, and whole-exome sequencing. MIBC patients with the high level of B7-H4 expression (B7-H4high) were found to possess an inferior overall and recurrence-free survival. Nonetheless, substantial clinical benefits of cisplatin-based chemotherapy and anti-PD-L1 immunotherapy were observed in these patients. After identifying a positive correlation between B7-H4 and tumor mutation burden (TMB), clinical benefits in B7-H4high TMBhigh subgroup were found to be the most upon PD-L1 blockade. Further studies revealed that B7-H4high subgroup was featured by non-inflamed immune contexture and cell cycle-related gene alterations. Despite adverse clinical outcomes, B7-H4high patients possessed superior responsiveness to chemotherapy and immunotherapy. B7-H4 stratification could also synergize with TMB to pinpoint the patients who benefited most from immunotherapy. The clinical exploration of B7-H4 as a companion predictor could allow clinicians to direct proper therapeutic agents to patients. • B7-H4 expression was proved to be an adverse prognosticator in MIBC. • B7-H4high patients had prolonged survival after chemotherapy or immunotherapy. • B7-H4high TMBhigh patients might benefit most from PD-L1 blockade. • B7-H4 correlated with non-inflamed immune contexture in MIBC. [ABSTRACT FROM AUTHOR]

• High angiogenesis signature yielded worse response to ICB but better response to ACT. • High angiogenesis signature correlated with an immunoevasive immunophenotype in MIBC. • TMBLowAngiogenesisHigh identified an ICB-resistant (ICBres) subgroup MIBC. • TGF-β signaling was enriched in ICBres MIBC. • Integration of angiogenesis signature and TMB could help identify patients sensitive to ICB. Muscle-invasive bladder cancer (MIBC) patients have benefitted greatly from immune checkpoint blockade (ICB) therapy. However, there is a pressing need to identify factors underlying the heterogeneity of clinical responses to ICB. We conducted a study on 848 MIBC patients from 4 independent cohorts to investigate the key biological characteristics affecting ICB responses. The IMvigor210 cohort (n = 234) was used to identify the key factor, followed by exploration of the correlation between tumor angiogenesis and immune suppression in the IMvigor210, TCGA (n = 391), and UNC-108 (n = 89) cohorts. The ZSHS cohort (n = 134) was used for validation. Additionally, we integrated angiogenesis signature with tumor mutation burden (TMB) to decipher the heterogeneity of clinical outcomes to ICB in MIBC patients. Our analysis revealed that nonresponders to PD-L1 blockade were enriched with angiogenesis signature. Furthermore, we observed a correlation between angiogenesis signature and decreased neoantigen load, downregulated T-cell antigen recognition, and noninflamed immunophenotype. We identified a subgroup of patients resistant to ICB, characterized by high angiogenesis signature and low tumor mutation burden (TMB), and found the activation of TGF-β signaling and downregulation of T-cell cytolytic signatures in this subgroup. The study concluded that angiogenesis signature is closely associated with an immunosuppressive microenvironment, leading to resistance to ICB therapy in MIBC patients. The study further suggested that the combination of angiogenesis signature and TMB can serve as an integrated biomarker for better stratification of patients' clinical outcomes to ICB therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: In tumor immune microenvironment, the functions of tumor-associated macrophages (TAMs), including phagocytosis and immunomodulatory, have attracted increasing attention recently. With the discovery of CD47-signal regulatory protein-α (SIRPα) as "don't eat me" signaling pathway, the role of novel subpopulation of TAMs expressing SIRPα has not been fully elucidated in a wide spectrum of solid tumors including bladder cancer. In this study, we investigated the prognostic and predictive implication of SIRPα+ TAMs regarding clinical outcomes and adjuvant chemotherapeutic benefit in muscle-invasive bladder cancer (MIBC), and preliminarily characterized the phenotypic features of SIRPα+ TAMs and its relationship with immune contexture.Materials and Methods: A total of 141 histochemical MIBC samples from Zhongshan Hospital (ZS), 45 fresh tissue samples, and 391 MIBC patients from TCGA database were enrolled in this study. SIRPα+ TAMs was evaluated by immunohistochemical staining of CD68 and SIRPα, and flow cytometry fluorescence staining.Results: Our results illustrated that SIRPα+ TAMs were enriched in MIBC specimens. Patients with high SIRPα+ TAMs infiltration suffered significant poor overall survival and recurrence-free survival (P = 0.0030 and P = 0.0282). SIRPα+ TAMs infiltration was an independent prognosticator in multivariate Cox model. Moreover, adjuvant chemotherapy (ACT) application showed significantly survival benefit in patients with low SIRPα+ TAMs infiltration (P = 0.0135). SIRPα+ TAMs with suppressive phenotype exhibited a positive correlation with immune tolerance and dysfunctional CD8+ T cells in MIBC.Conclusions: SIRPα+ TAMs infiltration indicated poor prognosis and ACT resistance in MIBC. Immunosuppressive SIRPα+ TAMs is closely related to immune evasion with exhausted T cells states, suggesting the prospect of SIRPα+ TAMs as a potential therapeutic target in MIBC. [ABSTRACT FROM AUTHOR]