Identification and validation of poor prognosis immunoevasive subtype of muscle-invasive bladder cancer with tumor-infiltrating podoplanin ⁺ cell abundance

Abstract

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 tumorinfiltrating 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.

Development and Validation of a Prognostic Model for Predicting Overall Survival in Patients With Bladder Cancer: A SEER-Based Study

“…Further, additional treatment has shown impacts on survival chance for patients with BLCA, which should be considered in clinical prediction models for evaluating prognosis (14,15). Researchers have injected tremendous enthusiasm into gene expression studies for prognostic models based on surgical samples of BLCA resection (16)(17)(18). However, batch effects on sequencing data via different platform are objective barriers for real-world validation, even with multiple statistical adjustment (19)(20)(21).…”

Prognostic Value of Podoplanin in Various Tumors

“…In pathology conditions, a growing body of evidence indicates that it plays an important role in tumorigenesis. [11][12][13] There is evidence that podoplanin correlates with tumor-associated lymphangiogenesis and cancer-associated fibroblasts (CAFs). [14][15][16] High expression of podoplanin has been observed in various kinds of tumor cells, such as oral cancer, esophageal cancer, lung cancer, cervical cancer, renal cancer, and cutaneous basal cell carcinoma.…”

Tumor-infiltrating podoplanin + cells in gastric cancer: clinical outcomes and association with immune contexture

“…Interestingly, our previous study revealed that M2 macrophages were positively correlated with PDPN + cells in muscle-invasive bladder cancer. 36 These findings suggest that tPDPNs might collaborate with macrophages in orchestrating the immunoevasive TME. As the main effector cells, CD8 + T cells play an important role in anti-tumor immunity.…”