METTL14 regulates CD8+T-cell activation and immune responses to anti-PD-1 therapy in lung cancer

World J Surg Oncol. 2024 May 10;22(1):128. doi: 10.1186/s12957-024-03402-9.

Abstract

Background: N6-methyladenosine (m6A) modification plays an important role in lung cancer. However, methyltransferase-like 14 (METTL14), which serves as the main component of the m6A complex, has been less reported to be involved in the immune microenvironment of lung cancer. This study aimed to analyze the relationship between METTL14 and the immune checkpoint inhibitor programmed death receptor 1 (PD-1) in lung cancer.

Methods: CCK-8, colony formation, transwell, wound healing, and flow cytometry assays were performed to explore the role of METTL14 in lung cancer progression in vitro. Furthermore, syngeneic model mice were treated with sh-METTL14 andan anti-PD-1 antibody to observe the effect of METTL14 on immunotherapy. Flow cytometry and immunohistochemical (IHC) staining were used to detect CD8 expression. RIP and MeRIP were performed to assess the relationship between METTL14 and HSD17B6. LLC cells and activated mouse PBMCs were cocultured in vitro to mimic immune cell infiltration in the tumor microenvironment. ELISA was used to detect IFN-γ and TNF-α levels.

Results: The online database GEPIA showed that high METTL14 expression indicated a poor prognosis in patients with lung cancer. In vitro assays suggested that METTL14 knockdown suppressed lung cancer progression. In vivo assays revealed that METTL14 knockdown inhibited tumor growth and enhanced the response to PD-1 immunotherapy. Furthermore, METTL14 knockdown enhanced CD8+T-cell activation and infiltration. More importantly, METTL14 knockdown increased the stability of HSD17B6 mRNA by reducing its m6A methylation. In addition, HSD17B6 overexpression promoted the activation of CD8+ T cells.

Conclusion: The disruption of METTL14 contributed to CD8+T-cell activation and the immunotherapy response to PD-1 via m6A modification of HSD17B6, thereby suppressing lung cancer progression.

Keywords: CD8+ T cell; HSD17B6; Lung cancer; METTL14; PD-1.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes* / immunology
  • CD8-Positive T-Lymphocytes* / metabolism
  • Cell Proliferation
  • Female
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Immunotherapy / methods
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Lymphocyte Activation
  • Methyltransferases* / genetics
  • Methyltransferases* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Prognosis
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / metabolism
  • Tumor Cells, Cultured
  • Tumor Microenvironment* / immunology

Substances

  • Immune Checkpoint Inhibitors
  • Methyltransferases
  • Mettl14 protein, mouse
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor