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Objectives Tumor necrosis receptor super family (TNFRSF) plays an important role in regulating the function of CD8+ T cells. In this study, we explored the clinical significance and immune profile of TNFRSF9+ CD8+ T cells in clear cell renal cell carcinoma (ccRCC) Methods The infiltration of immune cells was determined by immunohistochemistry in ZS cohort from our hospital and their prognostic value was further determined by Cox regression. Functional status of CD8+ T cells in ccRCC was determined by flow cytometry in 29 fresh tumor samples. In silico analysis on a TCGA cohort and other datasets was performed to further demonstrate our findings. Results High TNFRSF9+ CD8+ T cells infiltration was associated with inferior overall survival in ZS cohort (p = .0016) and TCGA-KIRC cohort (p = .018). TNFRSF9+ CD8+ T cells expressed higher exhaustion markers (PD-1, TIM-3, CTLA-4, and TIGIT), and effector markers (IFN-γ, GZMB, CD107a, and Ki-67), than their TNFRSF9 negative counterparts. In silico analysis indicated the expression of TNFRSF9 was significantly correlated with IFNG, GZMK, MKI-67, PDCD1, HAVCR2, TIGIT, and CTLA-4 in CD8+ T cells. However, higher TNFRSF9 signature was correlated with larger tumor size shrinkage (p = .003) and better progression-free survival (p = .012) in patients treated with nivolumab but not everolimus. Conclusion TNFRSF9+ CD8+ T cells, which possessed both exhaustion and effector phenotype, were identified as an adverse prognosticator in ccRCC. These cells enrichment was associated with better immunotherapy response which indicated these cells potentially be crucial in immunotherapy.

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