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Turning up the heat on non-immunoreactive tumors: pyroptosis influences the tumor immune microenvironment in bladder cancer

Oncogene volume 40, pages 6381–6393 (2021)Cite this article

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Abstract

The latest research confirms that cytotoxic lymphocytes rely on pyroptosis to kill tumor cells, suggesting that pyroptosis plays a vital role in immune response. However, the influence of pyroptosis on tumor microenvironment (TME) remodeling and immunotherapy is still unclear. We analyzed the variations in the expression of 28 pyroptosis-related molecules in pan-cancer tissues and normal tissues and the influence of genome changes. We investigated 2,214 bladder cancer samples and determined that there are three pyroptosis phenotypes in bladder cancer, and there are significant differences in cell infiltration characteristics in different pyroptosis phenotypes. Phenotypes with high expression of pyroptosis-related molecules are “hot tumors” with better immune function. We used a principal component analysis to measure the level of pyroptosis in patients with PyroScore, and confirmed that the PyroScore can predict the prognosis of bladder cancer patients, the sensitivity of the immune phenotype to chemotherapy, and the response to immunotherapy. Patients with a high PyroScore are more sensitive to chemotherapeutics such as cisplatin and gemcitabine, and have a better prognosis (HR = 0.7; 95%CI = 0.51–0.97, P = 0.041). Our study suggests a significant correlation between the expression imbalance of pyroptosis-related molecules and genome variation in various cancers and suggests pyroptosis plays an important role in modeling the TME. Evaluating pyroptosis modification patterns contributes to enhancing our understanding of TME infiltration and can guide more effective immunotherapy strategies.

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Fig. 1: Expression variation of pyroptosis-related molecules.
Fig. 2: Unsupervised learning to identify three classification keywords.
Fig. 3: Variations in immune-related genes and the infiltration characteristics of TME cells in the three pyroptosis phenotypes.
Fig. 4: Analysis of pyroptosis-related signal pathways.
Fig. 5: Clinical significance of PyroScore.
Fig. 6: PyroScore predicts the responsiveness of bladder cancer to chemotherapy and target therapy.
Fig. 7: GSDMB and CASP6 are related to the tumor immune microenvironment.

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Acknowledgements

We acknowledge the TCGA, GEO, and the ArrayExpress databases and their contributors. 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.

Funding

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, and the Wisdom Accumulation and Talent Cultivation Project of the Third xiangya hosipital of Central South University (BJ202001).

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  1. These authors contributed equally: Xingyu Chen, Haotian Chen.

Authors and Affiliations

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

    Xingyu Chen, Haotian Chen, Yao Zhang, Yuxing Zhu, YaXin Cheng, Rui Liu & Ke Cao

  2. Department of Learning, Informatics Management and Ethics, Karolinska institution, Solna, Sweden

    Honghui Yao

  3. Department of Hematology and Key Laboratory of Non-resolving Inflammation and Cancer of Hunan Province, Third Xiangya Hospital of Central South University, Changsha, 410013, China

    Kai Zhao

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

    Dong He

  5. Hunan Province of Hunan University of Chinese Medicine, Changsha, 410000, China

    Runshi Xu

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Contributions

Conceptualization, XC; methodology, XC and HC; investigation, XC, HC, HY, KZ, YZ, DH, YZ, YC, RL, and RX; writing—original drafts, XC; writing—review & editing, XC and HC; funding acquisition, KC; supervision, KC.

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Correspondence to Ke Cao.

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Chen, X., Chen, H., Yao, H. et al. Turning up the heat on non-immunoreactive tumors: pyroptosis influences the tumor immune microenvironment in bladder cancer. Oncogene 40, 6381–6393 (2021). https://doi.org/10.1038/s41388-021-02024-9

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