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Elevated circASCC3 limits antitumor immunity by sponging miR-432-5p to upregulate C5a in non-small cell lung cancer

Jian Gao1, Ling-Xian Zhang2, Yong-Qiang Ao1

  • 1Department of Thoracic Surgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai, 200032, PR China; Cancer Center, Zhongshan Hospital of Fudan University, Shanghai, 200032, PR China.

Cancer Letters
|June 6, 2022
PubMed

Insights

Circular RNAs like circASCC3 are upregulated in non-small cell lung cancer (NSCLC), driving resistance to anti-programmed cell death 1 (PD1) therapy by creating an immunosuppressive tumor microenvironment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Anti-programmed cell death 1 (PD1) therapy is a primary treatment for advanced non-small cell lung cancer (NSCLC).
  • However, a significant proportion of NSCLC patients exhibit resistance to anti-PD1 treatment, necessitating research into underlying mechanisms.
  • Circular RNAs (circRNAs) are emerging as critical regulators in various cancers, but their role in anti-PD1 resistance in NSCLC remains underexplored.

Purpose of the Study:

  • To investigate the role and mechanism of dysregulated circular RNAs (circRNAs) in anti-PD1 resistance in non-small cell lung cancer (NSCLC).
  • To evaluate the expression of circASCC3 in NSCLC tissues and its correlation with anti-PD1 treatment response.
  • To elucidate the functional impact of circASCC3 on NSCLC progression and the tumor microenvironment.

Main Methods:

  • Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to assess circASCC3 expression.
  • In vitro and in vivo experiments were conducted to determine the functions and mechanisms of circASCC3 in NSCLC.
  • Mechanistic studies involved investigating the interaction between circASCC3, miR-432-5p, and complement C5a levels.

Main Results:

  • CircASCC3 expression was significantly upregulated in NSCLC tissues compared to normal tissues.
  • Higher circASCC3 levels were observed in NSCLC patients refractory to anti-PD1 therapy versus sensitive patients.
  • Overexpression of circASCC3 promoted NSCLC cell malignancy and induced an immunosuppressive tumor microenvironment by sponging miR-432-5p and increasing C5a levels.

Conclusions:

  • CircASCC3 is upregulated in NSCLC and is associated with resistance to anti-PD1 immunotherapy.
  • CircASCC3 promotes NSCLC progression and immune evasion by modulating the miR-432-5p/C5a axis, thereby reshaping the tumor microenvironment.
  • CircASCC3 represents a potential therapeutic target for overcoming anti-PD1 resistance in NSCLC patients.
Keywords:
C5aImmune evasionNSCLCcircASCC3miR-432–5p

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