Identification of bladder cancer subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes

Wu, Jiyue; Zhang, Feilong; Zheng, **ang; Chen, Dongshan; Li, Zhen; Bi, Qing; Qiu, Xuemeng; Sun, Zejia; Wang, Wei

doi:10.1038/s41598-024-65198-8

Identification of bladder cancer subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes

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Published: 23 June 2024

Volume 14, article number 14431, (2024)
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Identification of bladder cancer subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes

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Jiyue Wu¹^na1,
Feilong Zhang¹^na1,
**ang Zheng¹^na1,
Dongshan Chen¹,
Zhen Li¹,
Qing Bi¹,
Xuemeng Qiu¹,
Zejia Sun¹ &
…
Wei Wang¹

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Abstract

Immunotherapy based on immune checkpoint genes (ICGs) has recently made significant progress in the treatment of bladder cancer patients, but many patients still cannot benefit from it. In the present study, we aimed to perform a comprehensive analysis of ICGs in bladder cancer tissues with the aim of evaluating patient responsiveness to immunotherapy and prognosis. We scored ICGs in each BLCA patient from TCGA and GEO databases by using ssGSEA and selected genes that were significantly associated with ICGs scores by using the WCGNA algorithm. NMF clustering analysis was performed to identify different bladder cancer molecular subtypes based on the expression of ICGs-related genes. Based on the immune related genes differentially expressed among subgroups, we further constructed a novel stratified model containing nine genes by uni-COX regression, LASSO regression, SVM algorithm and multi-COX regression. The model and the nomogram constructed based on the model can accurately predict the prognosis of bladder cancer patients. Besides, the patients classified based on this model have large differences in sensitivity to immunotherapy and chemotherapy, which can provide a reference for individualized treatment of bladder cancer.

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Introduction

Bladder cancer (BLCA) is the most common malignancy of the urinary system, characterized by high morbidity and mortality. According to statistics, there were 573,000 new diagnosed cases and 213,000 deaths of bladder cancer worldwide in 2020, ranking tenth among all cancers¹. According to the invasion depth of tumor, bladder cancer can be divided into non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), of which NMIBC accounts for about 75%². In recent years, despite the continuous improvement of surgical approaches, and the application of platinum-based neoadjuvant therapy and intravesical instillation of Bacillus Calmette Guerin (BCG) after operation have made significant progress in the treatment of bladder cancer, but the prognosis of BLCA patients is still far from satisfactory³. It has been reported that 40–80% of patients with NMIBC recur within 1 year after surgery, and 10–25% of these patients will progress to MIBC⁴. MIBC is prone to invade blood vessels, lymph nodes and develop distant metastases to form metastatic BLCA, and the five-year survival rates for muscle invasive MIBC and metastatic bladder cancer are estimated to be only 36–48% and 5–36%, respectively⁵. Therefore, it is urgent to develop effective and reliable prognostic and treatment strategies to improve the quality of life and long-term survival of BLCA patients.

With the development of gene sequencing technology, therapies for BLCA have been developed at the cellular and molecular levels. Studies have shown that BLCA has a relatively high total mutation spectrum compared to other types of tumors, and the number of neoantigens produced by it may also be higher. Therefore, administering immunotherapy to BLCA patients may be a potentially effective therapeutic measure^{Full size image}

CTSE inhibits the progression from NMBLC to MBLC

To clarify the relationship between CTSE gene and BLCA, the CTSE overexpression was constructed in two human bladder transitional cell carcinoma cells lines T24 and J82 by transfecting with Ad-CTSE adenovirus (Fig. 12A,B), and the expression level of CTSE in the transfected group increased significantly after the successful construction (Fig. 12C,D). The CCK-8 results showed that the cells activity of the CTSE over-expression in T24 cells and J82 cells were significantly lower than that of the control group (Fig. 12E,F). At the same time, the colony formation assay showed that the colony formation of the CTSE over-expression in T24 cells and J82 cells were significantly inhibited compared with the control group (Fig. 12G). These results all suggest that CTSE can inhibit the progression of tumor cells.

Discussion

With the increasing in BLCA diagnosed, it has become a major burden for health care in the world. Given its great heterogeneity at the cellular, molecular, and genomic levels, BLCA patients differ greatly in many aspects such as clinical characteristics and therapeutic responsiveness^16,17. Although significant progress has been made in the past decades with conventional treatment regimens, the survival rate and quality of life in BLCA patients have not improved significantly¹⁸. Immunotherapy is under extensive discussion in recent years, and immune checkpoint molecules are the key of immunotherapy. Immune checkpoint molecules are a kind of membrane protein that play a pivotal role in immune homeostasis by regulating the activation of immune cells¹⁹. Currently, several ICIs targeting immune checkpoints have shown great potential in the treatment of various malignancies including BLCA, and have been approved by the FDA for clinical application²⁰. However, despite the higher efficacy and tolerance of ICIs have been confirmed in BLCA patients, there are still many patients cannot benefit from them²¹. It has been suggested that the expression levels of classical ICGs such as CTLA4, PD-1, and PD-L1 may not accurately identify patients who may benefit from immunotherapy, and a comprehensive analysis of ICGs in bladder tumor tissues may be able to more accurately assess the responsiveness of BLCA patients to immunotherapy²².

In this study, we collected as many ICGs as possible mentioned in the published literature. BLCA patients in TCGA and GEO datasets were scored for ICGs according to the expression of 82 ICGs, and genes closely related to ICGs scores were obtained by the WCGNA algorithm. Based on the ICGs scores-related genes, the BLCA patients can be divided into two subgroups with significant differences in prognosis, clinical and immune characteristics by the NMF algorithm. The results of survival analysis showed that the OS and DSS of patients in C2 subgroup were significantly worse than C1 subgroup. In the comparison of clinical characteristics, the tumors with non-papillary tumors, higher pathological grade, advanced clinical stage, deeper bladder wall invasion and more severe lymph node metastasis were observed more commonly in C2 subgroup. The results of tumor microenvironment and immune cell infiltration analysis showed higher scores of immune, stromal and higher infiltration abundance of immune cells such as CD4 + T cells, CD8 + T cells and B cells in C2 subgroup. Besides, for the ICGs differentially expressed between the two subtypes, their expression was significantly higher in C2 subgroup than in C1 subgroup, and the results of the IPS immunotherapy analysis also confirmed that the response to ICIs did appear to be better in C2 patients than in C1 patients. The results of enrichment analysis showed that the differentially expressed genes between the two subtypes were mainly concentrated in a variety of immune related biological processes and signaling pathways.

The BLCA patients were classified into high-risk and low-risk groups based on the differentially expressed immune-related genes between the two subtypes using uni-COX, LASSO, SVM algorithms and multi-COX. In the TCGA and GEO patient cohorts, regardless of whether it is NMIBC or MIBC subtype, the OS of high-risk patients is worse than that of low-risk patients. The clinical correlation analysis showed that the risk score was closely related to age, pathological subtype, vascular lymph invasion, pathological grade, clinical stage and TNM stage of BLCA. Independent prognostic analysis showed that age, clinical stage of tumor and risk score were independent risk factors for BLCA. The nomogram constructed by integrating the above risk factors was used to predict the prognosis of BLCA patients, and the results were highly consistent with the actual survival rate of BLCA patients. To facilitate the individualized treatment of BLCA patients, we evaluated the responsiveness of two types of patients to immunotherapy by TIDE algorithm, IPS score and TMB analysis, and the results all showed that low-risk patients seemed more likely to benefit from immunotherapy. The above analysis results were further verified through IMvigor210 dataset, which showed that patients in the low-risk group had better responsiveness to immunotherapy than those in the high-risk group. The analysis of immune subtypes showed that there were more “inflamed” tumors in low-risk patients than in high-risk patients, and fewer “excluded” tumors than in high-risk patients.

The results of GSEA and GSVA enrichment analysis showed three distinct features including epithelial mesenchymal transition, hedgehog signaling pathway activation and angiogenesis in high-risk patients compared to the low-risk patients. Epithelial mesenchymal transition is considered be an important feature in the malignant progression of bladder cancer, which endows the urothelial cells with reprogramming, loss of apical polarity, and gains the ability to self-renewal, immune escape, and metastasis²³. Hedgehog signaling plays an important role in embryonic development, controlling cell proliferation and fate²⁴. Studies have shown that activation of hedgehog signaling pathway promotes the survival and renewal of cancer stem cells (CSCs) in BLCA and enhances the tolerance of BLCA to various chemotherapeutic agents²⁵. Besides, EMT may be induced by activating hedgehog signaling pathway at the early stage of tumor²⁶. Tumor angiogenesis is a complex process, which can inhibit the apoptosis of BLCA cells, promote their proliferation and migration, and enhance their immune escape²⁷.

For the nine genes in the model, FABP6, PDGFRA, NFATC1 and CTSE were found to be strongly associated with prognosis and clinical staging of BLCA patients²⁸. Consistent with this study, Lin et al. identified FABP6 as a protective gene in BLCA, and patients with low expression of FABP6 have a better prognosis²⁹. However, in another study, FABP6 was found to promote bladder cancer cell growth and cisplatin resistance. The specific reasons for these contradictory results are unclear so far, which deserves to be further explored in the future. PDGFRA has been widely explored in gastrointestinal tumors. Studies have shown that it can lead to the occurrence and progression of a variety of gastrointestinal tumors, and is considered as a potential target for anti-cancer treatment in gastric cancer³⁰. In BLCA, Mezheyeuski et al. found that PDGFRA was significantly up-regulated in tissues, and its expression level in tissues was also significantly related to the prognosis of BLCA patients³¹. NFATC1 increase BLCA to promote tumor cell growth/colony formation, and can also promote tumor migration and invasion by providing the expression of MMP2 and MMP9. In addition, NFATC1 was significantly higher in tumor tissues than in benign urothelium. The high expression of NFATC1 was significantly associated with poor prognosis. NFATC1 increased BLCA to promote tumor cell growth/colony formation and also promoted tumor migration and invasion by increasing expression of MMP2 and MMP9. In addition, NFATC1 was significantly higher in tumor tissues than in benign uroepithelium, and high NFATC1 expression was significantly associated with poor prognosis³². CTSE was identified as the most critical gene in the model. In recent years, CTSE was found to be differentially expressed in a variety of tumor tissues and its expression level was closely associated with the occurrence and development of tumors³³. For BLCA, in an earlier retrospective study, CTSE was considered as an independent prognostic marker for NMIBC and could be used to guide the treatment³⁴. Blaveri et al. found that CTSE was overexpressed in NMIBC compared with MIBC. In a long-term follow-up study of 693 NMIBC cases, it was confirmed that low CTSE expression was significantly associated with the progression of NMIBC to MIBC³⁵. Up to now, there are relatively few studies on the role of CTSE in the occurrence and development of BLCA. In our study, we found that overexpression of CTSE inhibited the proliferation and colony formation in different bladder cancer cell lines, which indicated the inhibition in tumor progression of CTSE.

In conclusion, in this study, we performed a comprehensive analysis of the expression profile of ICGs in BLCA tissues, and constructed an immune-related model based on the global landscape of ICGs. The high and low risk patients stratified by the model are different in many aspects such as prognosis prediction, clinical characteristics and treatment sensitivity. Early identification, timely intervention and individualized treatment of the two groups of patients based on the results of our model will help improve quality of life and long-term survival.

Data availability

The datasets analysed during the current study are available in the TCGA database (TCGA-BLCA, https://portal.gdc.cancer.gov) and GEO database (GSE13507 and GSE32894, https://www.ncbi.nlm.nih.gov/geo/). Further inquiries can be directed to the corresponding author.

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Acknowledgements

We would like to express our appreciation to TCGA and GEO database for providing the open-access databases utilized in this research study.

Funding

This study was supported by grants from the Bei**g Municipal Natural Science Foundation (7212040) and the National Natural Science Foundation of China (82070764).

Author information

These authors contributed equally: Jiyue Wu, Feilong Zhang and **ang Zheng.

Authors and Affiliations

Department of Urology, Bei**g Chaoyang Hospital, Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Bei**g, 100020, China
Jiyue Wu, Feilong Zhang, **ang Zheng, Dongshan Chen, Zhen Li, Qing Bi, Xuemeng Qiu, Zejia Sun & Wei Wang

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Jiyue Wu
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Feilong Zhang
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**ang Zheng
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Dongshan Chen
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Zhen Li
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Qing Bi
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Xuemeng Qiu
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Zejia Sun
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Wei Wang
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Contributions

All authors made a substantial, direct, and intellectual contribution to the work. J.W., F.Z. and X.Z. wrote the manuscript and designed the figures. Z.L., D.C., Q.B. and X.Q. revised the manuscript. Z.S. and W.W. supervised the manuscript. J.W., F.Z. and X.Z. contributed equally to the article.

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Correspondence to Zejia Sun or Wei Wang.

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Wu, J., Zhang, F., Zheng, X. et al. Identification of bladder cancer subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes. Sci Rep 14, 14431 (2024). https://doi.org/10.1038/s41598-024-65198-8

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Received: 08 December 2023
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Published: 23 June 2024
DOI: https://doi.org/10.1038/s41598-024-65198-8
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Identification of bladder cancer subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes

Abstract

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Identification of an immune gene-associated prognostic signature in patients with bladder cancer

Construction and validation of a gene signature related to bladder urothelial carcinoma based on immune gene analysis

Multi-cohort validation of Ascore: an anoikis-based prognostic signature for predicting disease progression and immunotherapy response in bladder cancer

Introduction

CTSE inhibits the progression from NMBLC to MBLC

Discussion

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Identification of bladder cancer subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes

Abstract

Similar content being viewed by others

Introduction

CTSE inhibits the progression from NMBLC to MBLC

Discussion

Data availability

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding authors

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Competing interests

Additional information

Publisher's note

Supplementary Information

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