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Background <p>As the objective overall response rate to immune checkpoint inhibitors (ICIs) is less than 30% in late stage or metastatic bladder cancer (BLCA), elucidating the intrinsic mechanisms of immune evasion is of great importance for the discovery of predictive and prognostic biomarkers and the exploration of novel targets for intervention. Recent studies have shown that <i>OBSCN</i> and the cytoskeletal protein it encodes, obscurin, play an important role in tumour progression. However, no studies have reported the role of <i>OBSCN</i> in BLCA.</p> Methods <p>RNA sequencing and clinical data were downloaded from multiple public databases including The Cancer Genome Atlas and the Gene Expression Omnibus. Immunohistochemistry (IHC) was performed on tissue microarrays including 80 BLCA patients from Shuguang Hospital. Kaplan-Meier curves with log-rank test, univariate and multivariate COX regression were performed to evaluate the prognostic efficacy of <i>OBSCN</i> expression. In vitro experiments were conducted to determine the role of <i>OBSCN</i> deficiency in promoting BLCA progression. Pan-cancer tumour immune microenvironment (TIME) analysis was performed to explore the potential correlation between <i>OBSCN</i> deficiency and immune evasion.</p> Results <p>Pan-cancers and single-cell sequencing analysis revealed that the expression level and proportion of <i>OBSCN</i> was significantly decreased in BLCA cells compared to normal urothelium. Survival curves showed that BLCA patients with low <i>OBSCN</i> expression had a worse prognosis, yet a better clinical response to PD-L1 ICIs. Gene set variation analysis and Gene set enrichment analysis revealed that epithelial-mesenchymal transition (EMT) and immune-related processes were significantly enriched in BLCA samples with low <i>OBSCN</i> expression. In vitro experiments identified that <i>OBSCN</i>-deficient BLCA cells enhanced invasion, migration and EMT. Pan-cancer analysis of TIME revealed that neoantigen, tumor mutation burden, CD8<sup>+</sup>T cells and immune checkpoints were significantly negatively associated with <i>OBSCN</i> expression. IHC and Western blot assay identified that BLCA samples with low OBSCN expression had more CD8<sup>+</sup> T-cell infiltration and higher PD-L1 expression.</p> Conclusions <p>This study confirmed that BLCA patients with low <i>OBSCN</i> expression had a worse prognosis but a superior response to ICIs, providing a reference for individualised treatment of BLCA patients.</p>

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Loss of OBSCN expression promotes bladder cancer progression but enhances the efficacy of PD-L1 inhibitors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月27日

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  • Tao Wang,
  • Tuanjie Guo,
  • Juanjuan Sun,
  • Xinyue Zang,
  • Lei Dong,
  • Jian Zhang,
  • Siteng Chen,
  • Guihua Chen,
  • Sicong Ma,
  • Xinyu Zhai,
  • Chuanmin Chu,
  • Chaofu Wang,
  • Xiang Wang,
  • Dongliang Xu,
  • Mingyue Tan

摘要

Background

As the objective overall response rate to immune checkpoint inhibitors (ICIs) is less than 30% in late stage or metastatic bladder cancer (BLCA), elucidating the intrinsic mechanisms of immune evasion is of great importance for the discovery of predictive and prognostic biomarkers and the exploration of novel targets for intervention. Recent studies have shown that OBSCN and the cytoskeletal protein it encodes, obscurin, play an important role in tumour progression. However, no studies have reported the role of OBSCN in BLCA.

Methods

RNA sequencing and clinical data were downloaded from multiple public databases including The Cancer Genome Atlas and the Gene Expression Omnibus. Immunohistochemistry (IHC) was performed on tissue microarrays including 80 BLCA patients from Shuguang Hospital. Kaplan-Meier curves with log-rank test, univariate and multivariate COX regression were performed to evaluate the prognostic efficacy of OBSCN expression. In vitro experiments were conducted to determine the role of OBSCN deficiency in promoting BLCA progression. Pan-cancer tumour immune microenvironment (TIME) analysis was performed to explore the potential correlation between OBSCN deficiency and immune evasion.

Results

Pan-cancers and single-cell sequencing analysis revealed that the expression level and proportion of OBSCN was significantly decreased in BLCA cells compared to normal urothelium. Survival curves showed that BLCA patients with low OBSCN expression had a worse prognosis, yet a better clinical response to PD-L1 ICIs. Gene set variation analysis and Gene set enrichment analysis revealed that epithelial-mesenchymal transition (EMT) and immune-related processes were significantly enriched in BLCA samples with low OBSCN expression. In vitro experiments identified that OBSCN-deficient BLCA cells enhanced invasion, migration and EMT. Pan-cancer analysis of TIME revealed that neoantigen, tumor mutation burden, CD8+T cells and immune checkpoints were significantly negatively associated with OBSCN expression. IHC and Western blot assay identified that BLCA samples with low OBSCN expression had more CD8+ T-cell infiltration and higher PD-L1 expression.

Conclusions

This study confirmed that BLCA patients with low OBSCN expression had a worse prognosis but a superior response to ICIs, providing a reference for individualised treatment of BLCA patients.