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Inhibition of STAT6 with Antisense Oligonucleotides Enhances the Systemic Antitumor Effects of Radiotherapy and

Kewen He1,2, Hampartsoum B Barsoumian2, Nahum Puebla-Osorio2

  • 1Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.

Cancer Immunology Research
|January 26, 2023
PubMed

Insights

Targeting STAT6 with an antisense oligonucleotide and hypofractionated radiotherapy reduced tumor growth and metastasis in non-small cell lung cancer models. This approach overcomes immune resistance and improves survival, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Immunology
  • Radiotherapy

Background:

  • Metastatic non-small cell lung cancer (NSCLC) exhibits limited response to radiotherapy (RT) and immunotherapy.
  • An immunosuppressive tumor microenvironment, characterized by M2 tumor-associated macrophages (TAMs), contributes to tumor progression and radioresistance.
  • M2 TAMs are activated via the STAT6 signaling pathway.

Purpose of the Study:

  • To investigate the efficacy of targeting STAT6 with an antisense oligonucleotide (ASO) combined with hypofractionated RT (hRT) in preclinical NSCLC models.
  • To evaluate the impact of this combination therapy on tumor growth, metastasis, and survival.
  • To elucidate the underlying mechanisms of action, including immune cell modulation.

Main Methods:

  • Utilized three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung adenocarcinomas).
  • Administered STAT6 ASO concurrently with hRT (3 fractions of 12 Gy each) to primary tumors.
  • Assessed tumor growth, lung metastasis, survival rates, and characterized the tumor microenvironment, including immune cell infiltration and cytokine levels.
  • Investigated the additive effects of anti-PD-1 immunotherapy.

Main Results:

  • STAT6 ASO plus hRT significantly slowed primary and abscopal tumor growth.
  • The combination therapy reduced lung metastases and extended overall survival.
  • Mechanistically, the treatment decreased M2 TAM infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and lowered TGFβ levels.
  • Addition of anti-PD-1 further augmented systemic antitumor responses.

Conclusions:

  • Targeting STAT6 with ASO and hRT demonstrates significant preclinical efficacy in immune-resistant NSCLC models.
  • This therapeutic strategy modulates the tumor microenvironment, enhancing anti-tumor immunity.
  • These findings provide a strong rationale for clinical trials evaluating this approach in patients with refractory NSCLC.

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