Oncogenic Role of HMGB1 as An Alarming in Robust Prediction of Immunotherapy Response in Colorectal Cancer

SIMPLE SUMMARY: The high mobility group box1 (HMGB1) protein operates as an alarm for danger. We explore the correlation between HMGB1 expression and the clinical survival status of patients receiving antitumor immunotherapy toward assessing the prognostic value in a multicancer context. We further conducted screening and identified four interacting genes that are targeted for binding by HMGB1-proteins and validate and contextualize the results in vitro. Additionally, HMGB1 function is also remarkably related to the tumor immune microenvironment and immune infiltration, especially regarding the high purity of stromal and immune cells in the tumor microenvironment (TME). In multicancer analysis, HMGB1 is also found linked with frequently genetic mutations and deletions, including in TMB and MSI which lead to resistance against antitumor immunotherapy and worse clinical prognosis among patients. The combination of HMGB1 expression with immune checkpoint molecules (ICPs), such as PD-L1, might present a novel immunology-based antitumor immunotherapy strategy. ABSTRACT: Objective: To assess the correlation between HMGB1 expression and the patient prognosis in a multicancer context. Methods: The potential oncogenic role of HMGB1 was explored in forty tumors through the TCGA, GEO, and Oncomine datasets. We analyzed the clinical prognostic value and antitumor immunotherapy of HMGB1 in a multicancer context using GEO (GSE111636). Results: High expression of HMGB1 is present in multicancer cases, and its low expression is closely associated with the prognostic survival of patients, in terms of both overall and disease-free survival in ACC and LUAD. Further investigation revealed that the high expression of gastric and lung cancer is closely associated with low risk and better prognosis of patients based on COX and Kaplan–Meier analysis of OS, FP and PPS. HMGB1 expression was found to be significantly correlated with cancer-associated fibroblast and CD8(+) T cell infiltration in the TME. The analysis of GO functional annotation/KEGG pathways indicates that HMGB1 may regulate tumor immunity-related pathways, such as the tumor immunotherapy response in colorectal cancer. The function of four genes as hubs are confirmed by in vitro HMGB1 knockdown which led to inhibition of cell proliferation and metastasis in SW620 and SW480 cells. Conclusion: HMGB1 is a potential novel biomarker for improving clinical prognosis and antitumor immunotherapy efficacy. CDK1, HMGB2, SSRP1, and H2AFV may serve as key nodes for HMGB1 in colorectal cancer.