The Relationship of Pyroptosis-Related Genes, Patient Outcomes, and Tumor-Infiltrating Cells in Bladder Urothelial Carcinoma (BLCA)

Ruiyan Xie; Ming Xie; Litong Zhu; Joanne W Y Chiu; Wayne Lam; Desmond Y H Yap

doi:10.3389/fphar.2022.930951

The Relationship of Pyroptosis-Related Genes, Patient Outcomes, and Tumor-Infiltrating Cells in Bladder Urothelial Carcinoma (BLCA)

Front Pharmacol. 2022 Jul 19:13:930951. doi: 10.3389/fphar.2022.930951. eCollection 2022.

Authors

Ruiyan Xie¹, Ming Xie², Litong Zhu¹, Joanne W Y Chiu³, Wayne Lam⁴, Desmond Y H Yap¹

Affiliations

¹ Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.
² Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
³ Division of Haematology, Medical Oncology and Haemopoietic Stem Cell Transplantation, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.
⁴ Division of Urology, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.

Abstract

Introduction: The role of pyroptosis and its effects on tumor-infiltrating cells (TICs) in the pathogenesis and treatment outcomes of patients with bladder urothelial carcinoma (BLCA) remains unclear. Methods: We conducted a bioinformatics analysis on the pyroptosis-related genes (PRGs) and TICs using data from public domains, and evaluated their impact on the pathogenesis and clinical outcomes of BLCA patients. A risk score based on PRGs and a prognostic risk model that incorporated patient demographics, tumor characteristics, and differentially expressed genes (DEGs) were developed. Results: Twenty-three DEGs of 52 PRGs were identified in BLCA and normal samples from the TCGA database. Missense mutations and single nucleotide polymorphisms in PRGs are the most common genetic abnormalities. Patients with high PRG risk scores showed an inferior survival compared to those with low risk scores. The prognostic risk model based on patient demographics, tumor characteristics, and DEGs showed good predictive values for patient survival at 1, 3, and 5 years in BLCA patients. Caspase-8 (CASP8) was the only intersection gene of the prognostic genes, DEGs, and different genes expressed in tissue. Patients with a high CASP8 expression had improved survival, and an increased CASP8 expression level was observed in activated CD4 memory T cells, follicular T helper cells, resting NK cells, M0 macrophages, and activated dendritic cells. CASP8 expression also showed a positive correlation with the IL7R expression-a key cell marker of CD4 memory T cells. CASP8 expression also showed correlations with immune checkpoints (PDCD1, CD274, and CTLA4) and response to immune checkpoint inhibitors. Conclusion: Our data suggest that PRGs, especially CASP8, showed strong associations with patient outcomes and TICs in BLCA. If validated, these results could potentially aid in the prognostication and guide treatment in BLCA patients.

Keywords: CASP8; bladder urothelial carcinoma; immune cells; immunotherapy; pyrotosis.