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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

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

The choice of chemo- or immuno-therapy for muscle-invasive bladder cancer (MIBC) patients remains contentious. Podoplanin is newly identified as an immune checkpoint which intrigues us to explore the clinical significance and immunoregulatory role of tumor-infiltrating podoplanin+ cells (PDPN+ cells) in MIBC. A retrospective analysis of 259 MIBC patients from Zhongshan Hospital (n = 141) and Shanghai Cancer Center (n = 118) was conducted. A total of 406 MIBC patients from TCGA database were enrolled to investigate the relationship between PDPN and molecular characterization. We found that tumor-infiltrating PDPN+ cell abundance indicated an inferior overall survival and recurrence-free survival. pT2 MIBC patients with PDPN+ cell low infiltration could benefit more from adjuvant chemotherapy (ACT). Increased PDPN+ cell infiltration was associated with diminished GZMB and TNF-α expression while correlated with expanded PD-1, PD-L1, LAG-3 and TIM-3 expression and tumor-promoting regulatory T cell and M2 macrophage infiltration. Tumors with high PDPN mRNA expression mainly presented luminal-infiltrated and basal-squamous subtypes (2017 TCGA classification) or stroma-rich and Ba/Sq subtypes (consensus classification). Elevated PDPN mRNA expression was associated with less FGFR3 activation signature and more T-cell-inflamed signature and EGFR activation signature. In conclusion, tumor-infiltrating PDPN+ cells could be applied as an independent prognosticator for clinical outcome and a predictive biomarker for suboptimal ACT responsiveness, which was also associated with immunosuppressive contexture infiltration. Intratumoral PDPN expression had a correlation with MIBC molecular classification and therapy-related signatures. The novel immune checkpoint PDPN should be considered as a possible immunotherapeutic target for MIBC.

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.

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

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

Which subgroups patients with muscle-invasive bladder cancer (MIBC) could benefit most from adjuvant chemotherapy (ACT) is blurred. Here we tried to stratify MIBC patients with tumor infiltrating mast cells (TIMs), explore the prognostic and predictive value of TIMs, and provide possible cellular explanations. We selected 259 MIBC patients who underwent radical cystectomy from two independent clinical centers between 2002 and 2014. TIMs were evaluated and prognostic and predictive value was assessed. The CIBERSORT method, Gene Set Enrichment Analysis (GSEA) and differential gene expression analyses were performed to explore the possible cellular mechanisms. TIMs infiltration was distinct between stromal and epithelial area of MIBC specimens. Patients with higher stromal TIMs had a significant worse overall survival and recurrence free survival (HR = 2.228, 95%CI: 1.467–3.550; P = 0.001 and HR = 1.984, 95%CI: 1.105–3.374; P = 0.016). More importantly, pT2 patients with low stromal TIMs tended to have a lower risk of death and recurrence after ACT (HR = 0.233, 95%CI: 0.020–0.814; P = 0.033 and HR = 0.180, 95%CI: 0.022–0.722; P = 0.031). A negative correlativity between TIMs and CD8 + T cells was identified on TCGA-BLCA cohort. Immunohistochemistry results validated that high stromal TIMs were negatively correlated with CD8 + T cells (Spearman’s rho = -0.215, P

CXC chemokine receptor 1 (CXCR1) signaling has been shown as an essential molecular nexus regarding cancer cell proliferation, tumor inflammation, and angiogenesis in clear cell renal cell carcinoma (ccRCC). The aim of this study was to investigate the prognostic significance of CXCR1 in patients with non-metastatic ccRCC. Data from 446 consecutive non-metastatic ccRCC patients, operated between 2003 and 2008 at a single institution, were evaluated retrospectively. The cohort was split into a training set (n = 223) and a validation set (n = 223). CXCR1 expression was assessed by immunohistochemistry staining and its association with clinicopathologic features and prognosis were evaluated. High CXCR1 epithelial expression presented prognostic value, and indicated poor overall survival (OS) (P = 0.010 and P = 0.015, respectively) and recurrence-free survival (P = 0.011 and P = 0.019, respectively) in the training and validation sets. The incorporation of CXCR1 into the T stage and SSIGN score would help to refine individual risk stratification. Multivariate analysis identified increased epithelial CXCR1 was statistically significantly associated with a poor outcome for OS (HR [95% CI] 1.808 [1.184–2.761]; P = 0.006) and RFS (HR [95% CI] 1.570 [1.076–2.290]; P = 0.019) in all non-metastatic ccRCC patients. Predictive nomograms were generated with identified independent prognosticators to assess patient overall survival and recurrence-free survival at 3, 5 and 10 y. Furthermore, high CXCR1 expression were correlated with elevated infiltrated neutrophils and enriched MMP family gene expression. To conclude, high CXCR1 level within epithelial area represented a potential independent negative prognostic factor regarding OS and RFS in non-metastatic ccRCC patients after nephrectomy.