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

Our plain-English summary of Blocking the GITR-GITRL pathway to overcome resistance to therapy in sarcomatoid malignant pleural mesothelioma, by M. Chan, L. Wu, Z. Yun, et al (Communications Biology, 2021).

The study

• Authors: M. Chan, L. Wu, Z. Yun, T.D. McKee, M. Cabanero, Y. Zhao, M. Kohno, J. Murakami, M. de Perrot
• Journal: Communications Biology
• Published: 2021;4(1):914
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2021. The Author(s).

In plain English

This was a laboratory study, plus an analysis of patient tumor samples, of why non-epithelioid (biphasic and sarcomatoid) malignant pleural mesothelioma resists treatment. It did not study asbestos exposure. The authors focused on two proteins, GITR and its partner GITRL. In three human mesothelioma cell lines, the sarcomatoid line (CRL5946) carried more GITR and GITRL than the other two, and cisplatin and Cs-137 radiation raised their levels. In immune-deficient mice, an antibody blocking GITR reduced tumor sphere formation by 55% for cisplatin-treated cells, 41% for irradiated cells and 33% for untreated cells. It also slowed growth of tumor tissue taken from one sarcomatoid patient, but not tissue from one epithelioid patient. In samples from 117 patients treated at the authors' Toronto institution, levels were higher in non-epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation followed by surgery, more intense GITR staining in tissue taken after radiation was associated with worse survival in non-epithelioid disease. The authors concluded that blocking this pathway could be a new treatment target for non-epithelioid mesothelioma, and said knock-in and knockout experiments are still needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using human mesothelioma cell lines, mouse xenografts and patient-derived xenografts, combined with analysis of archived patient tumor tissue and survival data
• Who was studied: Three human mesothelioma cell lines (CRL5820, CRL5915, CRL5946), which the authors' xenografts showed to be epithelioid, biphasic and sarcomatoid. Female NOD/SCID (immune-deficient) mice. Two patient-derived xenografts, one sarcomatoid (patient #17) and one epithelioid (patient #24). Tumor tissue from 117 malignant pleural mesothelioma patients (85 epithelioid, 29 biphasic, 2 sarcomatoid, 1 desmoplastic) who had surgery at the authors' Toronto institution between 2003 and 2015 or 2016.
• Exposure: No asbestos exposure was studied. The cells were treated with cisplatin (2 µg/mL) or Cs-137 irradiation (7.5 Gy) and with a neutralizing anti-GITR antibody. The patients were mostly pretreated with induction chemotherapy or high-dose hemithoracic radiation before surgery (the SMART approach).
• Main results:
  • In the cell lines, GITR and GITRL expression was higher in the sarcomatoid line (CRL5946) than in the other two lines. Cisplatin and Cs-137 irradiation increased GITR and GITRL expression.
  • In mice injected with CRL5946 cells, the anti-GITR antibody reduced intraperitoneal spheroid formation by 55% for cisplatin-treated cells, 41% for Cs-137-irradiated cells and 33% for untreated cells.
  • In patient-derived xenografts, the anti-GITR antibody decreased tumor size in sarcomatoid xenograft mice (n = 4) but had no effect on tumor size in epithelioid xenograft mice (n = 4).
  • Across all 117 patients, median survival was 28.6 months for epithelioid and 15.9 months for non-epithelioid patients.
  • In patient tumor tissue, GITR and GITRL were more highly expressed in non-epithelioid than in epithelioid tumors.
  • Among 73 patients uniformly treated with accelerated radiation followed by surgery, the intensity of GITR expression measured after radiation correlated negatively with survival in non-epithelioid patients.
  • In non-epithelioid SMART patients, predicting survival from expression gave an AUC of 0.77 for GITR (P = 0.06) and 0.83 for GITRL (P = 0.02). In epithelioid patients, GITRL gave an AUC of 0.646 (P = 0.08).
  • In epithelioid patients treated with SMART, high GITRL expression was associated with better survival.
• The authors' conclusion: The authors concluded that the GITR-GITRL pathway is a mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy, and that blocking it could be a new therapeutic target for non-epithelioid mesothelioma.
• Limitations the authors state:
  • The authors stated that the role of GITR/GITRL needs further study with knock-in and knockout experiments.
  • The authors noted that neutralizing GITR in patients might interfere with T-cell activation and the antitumor immune response.
  • The authors noted that the cell lines are classed by ATCC as epithelioid, and suggested that cell lines may lose their original characteristics during culture.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Sarcomatoid, Pleural Mesothelioma, Neoplasm, Pleura, Non-epithelioid, Biphasic Mesothelioma, Cisplatin, Apoptosis.

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