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Theranostics 2023; 13(13):4574-4600. doi:10.7150/thno.86928 This issue Cite

Research Paper

Histone deacetylase-mediated tumor microenvironment characteristics and synergistic immunotherapy in gastric cancer

Yilin Lin^1,2#, Xiangxiang Jing^1,2#, Zhihua Chen^3#, Xiaoxian Pan^4#, Duo Xu^1,2, Xiang Yu^1,2, Fengyun Zhong^1,2, Long Zhao^1,2, Changjiang Yang^1,2, Bo Wang^1,2, Shan Wang^1,2, Yingjiang Ye^1,2, Zhanlong Shen^1,2✉

1. Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, PR China.
2. Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, PR China.
3. Department of Gastrointestinal surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, PR China.
4. Department of Radiotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, PR China.
#: Equal contribution.

✉ Corresponding author: Zhanlong Shen, Peking University People's Hospital, Xizhimen South Street, Xicheng District, Beijing 100044, PR China. E-mail: shenzhanlongedu.cn.

Abstract

Background: Studies have shown that the expression of histone deacetylases (HDACs) is significantly related to the tumor microenvironment (TME) in gastric cancer. However, the expression of a single molecule or several molecules does not accurately reflect the TME characteristics or guide immunotherapy in gastric cancer.

Methods: We constructed an HDAC score (HDS) based on the expression level of HDACs. The single-cell transcriptome was used to analyze the underlying factors contributing to differences in immune infiltration between patients with a high and low HDS. In vitro and in vivo experiments validated the strategy of transforming cold tumors into hot tumors to guide immunotherapy.

Results: According to the expression characteristics of HDACs, we constructed an HDS model to characterize the TME. We found that patients with a high HDS had stronger immunogenicity and could benefit more from immunotherapy than those with a low score. The AUC value of the HDS combined with the combined positive score (CPS)for predicting the efficacy of immunotherapy was as high as 0.96. By single-cell and paired bulk transcriptome sequencing analysis, we found that the infiltration levels of CD4⁺ T cells, CD8⁺ T cells and NK cells were significantly decreased in the low HDS group, which may be induced by MYH11⁺ fibroblasts, CD234⁺ endothelial cells and CCL17⁺ pDCs via the MIF signaling pathway. Inhibition of the MIF signaling pathway was confirmed to potentially enhance immune infiltration. In addition, our analysis revealed that GPX4 inhibitors might be effective for patients with a low HDS. GPX4 knockout significantly inhibited PD-L1 expression and promoted the infiltration and activation of CD8⁺ T cells.

Conclusion: We constructed an HDS model based on the HDAC expression characteristics of gastric cancer. This model was used to evaluate TME characteristics and predict immunotherapy efficacy. Inhibition of the MIF signaling pathway in the TME and GPX4 expression in tumor cells may be an important strategy for cold tumor synergistic immunotherapy for gastric cancer.

Keywords: Histone deacetylases, Gastric cancer, Tumor microenvironment, Immunotherapy, Prognosis.

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