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CD8+ T effector and immune checkpoint signatures predict prognosis and responsiveness to immunotherapy in bladder cancer

Oncogene volume 40, pages 6223–6234 (2021)Cite this article

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Abstract

Immune-checkpoint blockade (ICB) has been routinely implemented to treat bladder cancer; however, most patients have little or no clinical benefit. In this study, 348 pretreated metastatic urothelial cancer samples from the IMvigor210 cohort were used to identify important genes significantly associated with CD8+ T effector and immune checkpoint signatures. The immune checkpoint inhibitor score (IMS) scoring system was constructed to predict the immunotherapy responsiveness. Transcriptome analysis confirmed that the high IMS score group had significant immune activation with better prognosis and higher immunotherapy responsiveness, which was a powerful biomarker for predicting the prognosis and responsiveness of ICB. Tumor immune dysfunction and exclusion (TIDE) scores were calculated using 2031 external bladder cancer samples for further validation. We selected the important Hub genes as potential therapeutic targets, and validated the genes using genomic, transcriptomic, immunomic, and other multi-omics methods. In addition, we construct a risk prediction model which could stratify patients with bladder cancer and predict patient prognosis and ICB treatment responsiveness. In conclusion, this study identified effective biomarkers for the prediction of immune checkpoint inhibitor treatment responsiveness in bladder cancer patients and provided new immunotherapeutic targets.

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Fig. 1: Network of co-expressed genes and module–trait relationships.
Fig. 2: Potential biological role of immune checkpoint inhibitor score (IMS) as a predictor.
Fig. 3: Immunotherapeutic responsiveness of immune checkpoint inhibitor score (IMS).
Fig. 4: Hub gene identification and evaluation of yellow module.
Fig. 5: Construction and verification of the immunotherapy prognostic classifier.
Fig. 6: Characteristics of prognostic model genes in anti-PD-L1 treatment cohort.
Fig. 7: Construction of nomogram for survival prediction.

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Acknowledgements

We would like to thank the TCGA, GEO, and TIMER databases for the availability of the data. We would like to thank TissueGnostics Aisa Pacific limited for their technical support, And the help of hongzhe Sun and Xiaojing Liu, the technical engineer. This work was supported by the National Natural Science Foundation of China (81874137), the science and technology innovation Program of Hunan Province (2020RC4011), the Outstanding Youth Foundation of Hunan Province (2018JJ1047), the Hunan Province Science and Technology Talent Promotion Project (2019TJ-Q10), Young Scholars of “Furong Scholar Program” in Hunan Province(206030106), and the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (BJ202001).

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Authors and Affiliations

  1. Department of Oncology, Third Xiangya Hospital, Central South University, 283 Tongzipo Road, Changsha, 410013, China

    Xingyu Chen, Yao Zhang, Haotian Chen, Yuxing Zhu, YaXin Cheng, Rui Liu, Rongrong Zhu, Lian Gong, Mengqing Xiao, Zhanwang Wang, Liping Deng & Ke Cao

  2. Medical school, Hunan University of Chinese Medicine, No. 300, Xueshi Road, Hanpu kejiao Park, Yuelu District, Changsha, 410208, China

    Runshi Xu

  3. Department of Respiration, The Second People’s Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, 410000, China

    Dong He

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Contributions

XYC and KC designed the study, XYC analyzed and interpreted the data, XYC, XRS and CHT wrote this manuscript. HD, ZY, CHT, ZYX, CYX and LR edited and revised the manuscript. All authors have seen and approved the final version of the manuscript.

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Correspondence to Ke Cao.

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Chen, X., Xu, R., He, D. et al. CD8+ T effector and immune checkpoint signatures predict prognosis and responsiveness to immunotherapy in bladder cancer. Oncogene 40, 6223–6234 (2021). https://doi.org/10.1038/s41388-021-02019-6

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