2. Academic Validation
  3. ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages

ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages

  • J Exp Clin Cancer Res. 2024 Jun 14;43(1):164. doi: 10.1186/s13046-024-03073-0.
Xin Hua # 1 2,  Qiuli Xu # 1 2,  Ranpu Wu # 1 2,  Wei Sun 1 2,  Yanli Gu 2,  Suhua Zhu 2,  Xin Liu 2,  Tangfeng Lv 3 4,  Yong Song 5 6
Affiliations

Affiliations

  • 1 Medical School of Southeast University, Nanjing, 210003, China.
  • 2 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China.
  • 3 Medical School of Southeast University, Nanjing, 210003, China. bairoushui@163.com.
  • 4 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China. bairoushui@163.com.
  • 5 Medical School of Southeast University, Nanjing, 210003, China. yong.song@nju.edu.cn.
  • 6 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China. yong.song@nju.edu.cn.
  • # Contributed equally.
PMID: 38872221 DOI: 10.1186/s13046-024-03073-0
Abstract

Background: Understanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with Cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung Cancer. However, its role in the tumor microenvironment is unknown.

Methods: Datasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA Sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung Cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung Cancer.

Results: ALKBH5 was upregulated in primary non-small cell lung Cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung Cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in Cancer cells.

Conclusions: ALKBH5 promotes non-small cell lung Cancer progression by regulating Cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy.

Keywords

ALKBH5; JAK2/p-STAT3 pathway; N6-methyladenosine demethylase; Non-small cell lung cancer; Tumor microenvironment; Tumor-associated macrophage.

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