Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM)

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options.
• Signal transducer and activator of transcription 3 (STAT3) is implicated in various cancers and cancer stem cell maintenance.
• STAT3 activation is observed in MPM, highlighting its potential as a therapeutic target.

Purpose of the Study:

• To investigate the role of STAT3 in MPM cell growth and gene expression.
• To evaluate the efficacy of STAT3 inhibition as a therapeutic strategy for MPM.
• To explore the impact of STAT3 inhibition on the tumor microenvironment and immune response.

Main Methods:

• Utilized preclinical MPM models, including cell lines and primary-derived cultures.
• Employed small hairpin RNAs (shRNAs) and pharmacologic inhibitors (atovaquone, pyrimethamine) to target STAT3.
• Assessed cell viability, tumor growth in microfluidic and in vivo xenotransplant models.
• Analyzed gene expression changes related to STAT3 signaling, cell cycle, p53 response, and immunomodulation.

Main Results:

• STAT3 inhibition significantly reduced MPM cell growth and viability in established and primary-derived lines.
• Atovaquone demonstrated efficacy in reducing tumor growth in both microfluidic and in vivo MPM models.
• STAT3 inhibition modulated gene expression, affecting cell cycle progression, p53 response, and immune regulatory pathways.
• Targeting STAT3 led to the upregulation of immunoregulatory genes like ICOSLG, potentially enhancing anti-tumor immunity.

Conclusions:

• STAT3 plays a critical role in MPM progression and warrants therapeutic targeting.
• STAT3 inhibitors, such as atovaquone and pyrimethamine, show significant anti-tumor activity against MPM.
• STAT3 inhibition may enhance anti-tumor immune responses by modulating the tumor microenvironment.
• STAT3 inhibitors represent a promising therapeutic avenue for malignant pleural mesothelioma.