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Blocking the GITR-GITRL pathway to overcome resistance to therapy in sarcomatoid malignant pleural mesothelioma

Meilin Chan1,2,3,4, Licun Wu2, Zhihong Yun2

  • 1Division of Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Communications Biology
|July 27, 2021
PubMed

Insights

The GITR-GITRL pathway drives growth and therapy resistance in malignant pleural mesothelioma (MPM), particularly in sarcomatoid types. Blocking this pathway offers a potential new treatment strategy for non-epithelioid MPM.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Malignant pleural mesothelioma (MPM) is an aggressive cancer.
  • Non-epithelioid MPM subtypes exhibit significant resistance to conventional therapies.
  • The role of the GITR-GITRL pathway in MPM therapy resistance is largely unexplored.

Purpose of the Study:

  • To investigate the involvement of the GITR-GITRL pathway in mediating therapeutic resistance in MPM.
  • To explore the GITR-GITRL pathway as a potential therapeutic target for non-epithelioid MPM.

Main Methods:

  • Comparative analysis of GITR and GITRL expression in MPM cell lines and patient tumors.
  • Assessment of GITR-GITRL pathway activity following treatment with cisplatin and irradiation.
  • Transcriptome analysis to elucidate pathway functions.
  • In vitro and in vivo spheroid formation assays.
  • Evaluation of anti-GITR neutralizing antibodies in patient-derived xenograft (PDX) models.
  • Correlation analysis of GITR expression with patient survival data.

Main Results:

  • Higher GITR and GITRL expression observed in sarcomatoid MPM cell lines and non-epithelioid tumors.
  • Cisplatin and irradiation treatments upregulated GITR and GITRL expression on tumor cells.
  • The GITR-GITRL pathway promotes tumor growth and inhibits apoptosis.
  • Increased spheroid formation in GITR/GITRL-positive cells suggests enhanced tumor stemness.
  • Anti-GITR antibodies reduced tumor growth in sarcomatoid MPM PDX models.
  • High post-radiation GITR expression correlated with poorer survival in non-epithelioid MPM patients.

Conclusions:

  • The GITR-GITRL pathway is a key mediator of autocrine proliferation and therapy resistance in sarcomatoid mesothelioma.
  • This pathway is linked to tumor stemness and contributes to treatment unresponsiveness.
  • Targeting the GITR-GITRL pathway presents a promising novel therapeutic strategy for non-epithelioid MPM.

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