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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 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.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC7759386 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC.MethodsThis study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status.ResultsWe observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules.ConclusionCD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

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

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Dataset Information

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

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OmicsDI is part of the ELIXIR infrastructure

Tweets

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