Pyroptosis-Related Patterns Predict Tumor Immune Landscape and Immunotherapy Response in Bladder Cancer

Yilin Yan; Xiangqian Cao; Zeyi Wang; Zhengnan Huang; Jinming Cai; Pengfei Tang; Chenkai Yang; Fang Zhang; Shujie Xia; Bing Shen

doi:10.3389/fmolb.2022.815290

Pyroptosis-Related Patterns Predict Tumor Immune Landscape and Immunotherapy Response in Bladder Cancer

Front Mol Biosci. 2022 Apr 26:9:815290. doi: 10.3389/fmolb.2022.815290. eCollection 2022.

Authors

Yilin Yan¹, Xiangqian Cao¹, Zeyi Wang², Zhengnan Huang¹, Jinming Cai¹, Pengfei Tang², Chenkai Yang¹, Fang Zhang¹, Shujie Xia^{1

3}, Bing Shen¹

Affiliations

¹ Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
² Department of Urology, Shanghai General Hospital Affiliated to Nanjing Medical University, Shanghai, China.
³ Institute of Urology, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Background: Bladder cancer (BC) is a leading cause of death from malignancy, with significant heterogeneity in the immunotherapeutic responsiveness of advanced status. Pyroptosis, a newly discovered inflammatory programmed cell death, is confirmed to play an indispensable role in tumorigenesis and anti-tumor activity. However, the effect of pyroptosis on the tumor-immune landscape remodeling and immunotherapy in BC remains elusive. Methods: We comprehensively evaluated the mRNA expression and genomic alterations of 33 pyroptosis-related genes (PRGs) in BC and evaluated the patterns of pyroptosis in publicly available BC datasets. An unsupervised clustering method was used to classify patients into distinct patterns. Then, we established a pyroptosis-related signature score (PS-score) model to quantify the pyroptosis-related patterns of individual BC patients using principal component analysis. Furthermore, we correlated the patterns with the immune landscape and response efficacy of immunotherapy. Results: Two pyroptosis-related patterns were identified in BC, and distinct patterns showed various immune characteristics. Patterns with a high expression level of PRGs exhibited a survival advantage and showed higher infiltration of cytotoxic lymphocytes. Tumors with a low PS-score were characterized by high tumor-infiltrating lymphocytes and considered "hot." Further analysis revealed that the PS-score was an independent prognostic factor and could predict the response to immunotherapy for patients with advanced BC. We found a significant positive association between AHNAK2, AHNAK nucleoprotein 2, expression, and PS-score. Functional assays showed that AHNAK2 knockdown was correlated with attenuated invasive ability. Conclusion: This work comprehensively demonstrated the potential function of pyroptosis-related patterns in the bladder tumor-immune landscape and identified their therapeutic liability in immunotherapy. Our study enhanced our understanding of the immune landscape and provided a new approach toward more effective immunotherapy strategies.

Keywords: bladder cancer; immunotherapy; microenvironment; pyroptosis; score.