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

Commun Biol. 2021 Jul 26;4(1):914. doi: 10.1038/s42003-021-02430-5.


Malignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are particularly resistant to therapy. We investigated the role of the GITR-GITRL pathway in mediating the resistance to therapy. We found that GITR and GITRL expressions were higher in the sarcomatoid cell line (CRL5946) than in non-sarcomatoid cell lines (CRL5915 and CRL5820), and that cisplatin and Cs-137 irradiation increased GITR and GITRL expressions on tumor cells. Transcriptome analysis demonstrated that the GITR-GITRL pathway was promoting tumor growth and inhibiting cell apoptosis. Furthermore, GITR+ and GITRL+ cells demonstrated increased spheroid formation in vitro and in vivo. Using patient derived xenografts (PDXs), we demonstrated that anti-GITR neutralizing antibodies attenuated tumor growth in sarcomatoid PDX mice. Tumor immunostaining demonstrated higher levels of GITR and GITRL expressions in non-epithelioid compared to epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation therapy followed by surgery, the intensity of GITR expression after radiation negatively correlated with survival in non-epithelioid MPM patients. In conclusion, the GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. Blocking the GITR-GITRL pathway could be a new therapeutic target for non-epithelioid mesothelioma.

Trial registration: NCT00797719.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cesium Radioisotopes / pharmacology*
  • Cisplatin / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Glucocorticoid-Induced TNFR-Related Protein / genetics*
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism
  • Humans
  • Mesothelioma, Malignant / genetics*
  • Mesothelioma, Malignant / therapy
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Tumor Necrosis Factors / genetics*
  • Tumor Necrosis Factors / metabolism


  • Antineoplastic Agents
  • Cesium Radioisotopes
  • Glucocorticoid-Induced TNFR-Related Protein
  • Tnfrsf18 protein, mouse
  • Tnfsf18 protein, mouse
  • Tumor Necrosis Factors
  • Cesium-137
  • Cisplatin

Associated data