Comprehensive Pan-Cancer Analyses of Immunogenic Cell Death as a Biomarker in Predicting Prognosis and Therapeutic Response

SIMPLE SUMMARY: Immunogenic cell death (ICD) is an important mechanism underlying anti-cancer therapy response by activating the immune system. However, the landscape and predictive value of ICD among cancers remain to be elucidated. In this study, we carried out a comprehensive analysis integrating genomic, proteomic and epigenetics data across 33 cancer types, 31 normal tissue types and 1406 cancer cell lines. We found that the expression level of ICD-related genes was regulated by methylation and transcriptional regulators. We figured out the most valuable ICD-related markers in predicting prognosis in cancer patients and developed a model for practical use. We also defined the ICD score and found that it was a reliable marker in predicting survival, chemotherapy and immunotherapy across cancer patients. Further exploration using single-cell RNA-seq data indicated that T cell might remodel the tumor microenvironment by turning a “cold” tumor into a “hot” one in an ICD-dependent manner. Moreover, we also discovered several ICD-related therapeutic targets including IGF2BP3 which might benefit cancer patients who could hardly respond to immunotherapy. ABSTRACT: Immunogenic cell death (ICD), a form of regulated cell death, is related to anticancer therapy. Due to the absence of widely accepted markers, characterizing ICD-related phenotypes across cancer types remained unexplored. Here, we defined the ICD score to delineate the ICD landscape across 33 cancerous types and 31 normal tissue types based on transcriptomic, proteomic and epigenetics data from multiple databases. We found that ICD score showed cancer type-specific association with genomic and immune features. Importantly, the ICD score had the potential to predict therapy response and patient prognosis in multiple cancer types. We also developed an ICD-related prognostic model by machine learning and cox regression analysis. Single-cell level analysis revealed intra-tumor ICD state heterogeneity and communication between ICD-based clusters of T cells and other immune cells in the tumor microenvironment in colon cancer. For the first time, we identified IGF2BP3 as a potential ICD regulator in colon cancer. In conclusion, our study provides a comprehensive framework for evaluating the relation between ICD and clinical relevance, gaining insights into identification of ICD as a potential cancer-related biomarker and therapeutic target.