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The circadian rhythm key gene ARNTL2: a novel prognostic biomarker for immunosuppressive tumor microenvironment

Gujie Wu1, Hefei Ren2, Qin Hu1

  • 1Department of Respiratory medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.

Frontiers in Immunology
|June 5, 2023
PubMed
Summary

Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) promotes tumor growth and creates an immunosuppressive tumor microenvironment. Targeting ARNTL2 may improve immunotherapy response and patient survival in cancer.

Keywords:
ARNTL2human cancersimmunosuppressive tumor microenvironmentimmunotherapyprognosis

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Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology
  • Circadian Biology

Background:

  • Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) is a key circadian clock gene.
  • Its role in cancer, particularly the tumor immune microenvironment (TIME) and immunotherapy, is not well understood.

Purpose of the Study:

  • To investigate the role of ARNTL2 expression in cancer prognosis and immune response.
  • To explore ARNTL2's impact on the tumor immune microenvironment and its potential as a therapeutic target.

Main Methods:

  • Integrated multi-omics data from public databases (TCGA, CCLE, GTEx, Human Protein Atlas, cBioPortal, TIMER, ImmuCellAI).
  • Analyzed data from a clinical study and three immunotherapy cohorts.
  • Performed in vitro experiments and gene-set enrichment analyses (GSEA, GSVA).

Main Results:

  • ARNTL2 is aberrantly expressed in most tumors, correlating with poor survival and advanced pathologic staging.
  • ARNTL2 promotes cell proliferation via cell cycle regulation and influences innate/adaptive immunity.
  • Overexpression of ARNTL2 creates an immunosuppressive TIME, increasing immunosuppressive cells (Tregs, TAMs, CAFs) and pathways.
  • Low ARNTL2 expression improved response and survival in patients receiving immune checkpoint inhibitors (ICI).

Conclusions:

  • ARNTL2 acts as a potential oncogene in tumorigenesis and cancer immunity.
  • Elevated ARNTL2 signifies an immunosuppressive tumor microenvironment.
  • Targeting ARNTL2 combined with ICI therapy may enhance anti-cancer treatment efficacy.