Abstract
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.
Highlights
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura
We discovered that the expression of Glucocorticoid-Induced TNFR-Related Protein Ligand (GITRL, Tnfsf18) could be induced by radiation and chemotherapy and be a marker of stem-like cells associated with resistance to chemotherapy or radiotherapy in murine mesothelioma[8]
GITR/GITRL expression is associated with resistance to chemo and radiotherapy in human mesothelioma cell lines
Summary
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are resistant to therapy. The GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. A novel therapeutic approach with Surgery for Mesothelioma After Radiation Therapy (SMART) demonstrated encouraging outcome in epithelioid MPM with a median survival of 36 months[4]. It is well established that the sarcomatoid and biphasic mesothelioma subtypes are refractory to conventional therapies including surgery, chemotherapy, and radiotherapy with median survivals of less than 12 months in large trials[5,6]. Expression of GITR/GITRL may be a mechanism of immune escape developed by cancer cells. We aimed to elucidate the role of GITR/GITRL as a potential mechanism of resistance to therapy in mesothelioma
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