1. Academic Validation
  2. HMGB1 inhibits the IFN-γ-induced PD-L1 expression in NSCLC

HMGB1 inhibits the IFN-γ-induced PD-L1 expression in NSCLC

  • J Immunol. 2025 Jun 28:vkaf125. doi: 10.1093/jimmun/vkaf125.
Shumin Wang 1 Feng Li 1 Liubo Zhang 1 Yu Ping 1 Wenhao Hu 2 Qun Gao 3 Qitai Zhao 1 Kai Zhang 1 Yibo Huang 1 Bin Zhang 4 Yi Zhang 1 2 5 6
Affiliations

Affiliations

  • 1 Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China.
  • 2 School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China.
  • 3 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.
  • 4 Division of Hematology/Oncology, Department of Medicine, School of Medicine, Northwestern University, Chicago, IL, United States.
  • 5 State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, P.R. China.
  • 6 Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, P.R. China.
Abstract

T cells are the most important cytotoxic cells involved in antitumor immune responses. After recognizing the major histocompatibility complex (MHC)-peptide complex, cytokines including interferon-γ (IFN-γ) are released to kill tumor cells. However, IFN-γ can also induce tumor cells to express PD-L1. This molecule can bind to PD-1 on the surface of T cells to exert inhibitory functions. In response to stimuli, like chemoradiotherapy or immunotherapy, tumor cells release damage-associated molecular patterns, including high-mobility group protein B1 (HMGB1). Our previous studies revealed that HMGB1 can increase the antitumor activity of T cells and enhance the secretion of cytokines, including IFN-γ. However, the effect of HMGB1 on PD-L1 expression in non-small cell lung Cancer remains unclear. Here, we examined the expression of HMGB1 and PD-L1 in tumor tissue slices of patients with non-small cell lung Cancer with high expression of IFN-γ and observed that they exhibited a negative correlation, which was also verified by our analysis in The Cancer Genome Atlas. In vitro experiments demonstrated that HMGB1 could bind to RAGE (receptor for advanced glycation end products) and inhibit IFN-γ induction of PD-L1 by inhibiting the JAK1/STAT3 pathway. In vitro and in vivo experiments indicated that HMGB1 enhanced the antitumor effects of chimeric antigen receptor T cells and inhibited tumor growth. These results showed that HMGB1 inhibited IFN-γ-induced PD-L1 expression, thereby enhancing the antitumor effects of T cells, and confirmed the role of HMGB1 as a prognostic indicator for lung Cancer treated with chimeric antigen receptor T cells.

Keywords

CD8+ T cells; high-mobility group protein B1; programmed cell death ligand 1.

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