Tumor Necrosis Factor-α- Dependent Inflammation Upregulates High Mobility Group Box 1 To Induce Tumor Promotion and Anti-Programmed Cell Death Protein-1 Immunotherapy Resistance in Lung Adenocarcinoma

Tumor-associated chronic lung inflammation depends on tumor necrosis factor (TNF)-a to activate several cytokines as part of an inflammatory loop, which plays a critical role in tumor progression in lung adenocarcinoma. High mobility group box 1 (HMGB1) is a cytokine that mediates inflammation. Whether TNF-a-induced inflammation regulates HMGB1 to contribute to tumor progression and promotion in lung adenocarcinoma remains unclear. Thus, human samples and a urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mouse model were used to explore the involvement of HMGB1 in tumorigenesis and tumor progression and efficacy of anti -programmed cell death protein (PD)-1 immunotherapy. High levels of HMGB1 were observed in human lung adenocarcinoma associated with poor overall survival in patients. HMGB1 upregulation was positively correlated with TNF-a-related inflammation and TIM-3 & thorn; infiltration. TNFa upregulated intracellular and extracellular HMGB1 expression to contribute to tumor promotion in A549 cells in vitro. Using a urethane-induced IDLA mouse model, we found HMGB1 upregulation was associated with increased TIM-3 & thorn; T-cell infiltration. Blocking TNF-a-dependent inflammation downregulated HMGB1 expression and inhibited tumorigenesis in the IDLA model. Anti-PD-1 treatment alone did not inhibit tumor growth in the TNF-a-dependent IDLA, whereas anti-PD-1 combined with TNF-a blockade overcame anti-PD-1 immunotherapy resistance. Furthermore, anti-PD-1 combined with anti-HMGB1 also inhibited tumor growth in IDLA, suggesting that increased HMGB1 release by TNF-a contributes to the resistance of anti-PD-1 immunotherapy in IDLA. Thus, tumor-associated TNF-a-dependent inflammation upregulated intracellular and extracellular HMGB1 expression in an inflammatory loop, contributing to tumor promotion and anti-PD-1 immunotherapy resistance in lung adenocarcinoma. (c) 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.