Immunogenic Cell Death Mediation Patterns Reveal Novel Paradigm for Characterizing the Immune Microenvironment and Immunotherapeutic Responses in Bladder Cancer

Immunogenic cell death (ICD) plays an important role in several malignancies. However, the role of ICD-mediated patterns in bladder cancer (BCA) remains unknown. For assessing the ICD-mediated patterns based on the expression of IRGs, 4 large BCA cohorts were obtained. The ICD-mediated patterns of individual samples were quantified as an ICD score by principal component analysis. The correlations of the ICD-mediated patterns with the tumor immune microenvironment (TIME) and responses to immunotherapy were comprehensively evaluated. The IRGs with predictive prognostic values were further validated by loss of function assays. Two distinct ICD-mediated patterns were established, showing distinct clinical features and immune microenvironment features. Although ICD cluster A was associated with a poor prognosis with a high ICD score, it showed an immune activation state with a more favorable response to immunotherapy and treatment that induced ICD. The ICD-related gene, CALR, was significantly upregulated in the T24 BCA cell line relative to the control SV-HUC-1 cells. Knocking down CALR suppressed T24 cell viability and caused ER stress. We identified the existence of distinct ICD-mediated patterns in BCA closely associated with the remodeling of the TIME. Further in-depth examination of ICD-related features is warranted to obtain a broader prospect for therapeutic innovations and improved prognosis of BCA.