Trabectedin overrides osteosarcoma differentiative block and reprograms the tumor immune environment enabling effective combination with immune checkpoint inhibitors

Chiara Ratti, Laura Botti, Valeria Cancila, Silvia Galvan, Ilaria Torselli, Cecilia Garofalo, Maria Cristina Manara, Lucia Bongiovanni, Cesare F. Valenti, Alessia Burocchi, Mariella Parenza, Barbara Cappetti, Sabina Sangaletti, Claudio Tripodo, Katia Scotlandi, Mario P. Colombo, Claudia Chiodoni

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer. Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression. Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors.

Original languageEnglish
Pages (from-to)5149-5161
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number17
DOIs
Publication statusPublished - Sep 1 2017

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trabectedin
Osteosarcoma
Neoplasms
Lung
Neoplasm Metastasis
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Bone and Bones
Blocking Antibodies
Tumor Microenvironment
Therapeutics
Osteoblasts
Sarcoma
Ovarian Neoplasms
Immunotherapy
Cell Differentiation
Immune System
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Trabectedin overrides osteosarcoma differentiative block and reprograms the tumor immune environment enabling effective combination with immune checkpoint inhibitors. / Ratti, Chiara; Botti, Laura; Cancila, Valeria; Galvan, Silvia; Torselli, Ilaria; Garofalo, Cecilia; Manara, Maria Cristina; Bongiovanni, Lucia; Valenti, Cesare F.; Burocchi, Alessia; Parenza, Mariella; Cappetti, Barbara; Sangaletti, Sabina; Tripodo, Claudio; Scotlandi, Katia; Colombo, Mario P.; Chiodoni, Claudia.

In: Clinical Cancer Research, Vol. 23, No. 17, 01.09.2017, p. 5149-5161.

Research output: Contribution to journalArticle

Ratti, Chiara ; Botti, Laura ; Cancila, Valeria ; Galvan, Silvia ; Torselli, Ilaria ; Garofalo, Cecilia ; Manara, Maria Cristina ; Bongiovanni, Lucia ; Valenti, Cesare F. ; Burocchi, Alessia ; Parenza, Mariella ; Cappetti, Barbara ; Sangaletti, Sabina ; Tripodo, Claudio ; Scotlandi, Katia ; Colombo, Mario P. ; Chiodoni, Claudia. / Trabectedin overrides osteosarcoma differentiative block and reprograms the tumor immune environment enabling effective combination with immune checkpoint inhibitors. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 17. pp. 5149-5161.
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T1 - Trabectedin overrides osteosarcoma differentiative block and reprograms the tumor immune environment enabling effective combination with immune checkpoint inhibitors

AU - Ratti, Chiara

AU - Botti, Laura

AU - Cancila, Valeria

AU - Galvan, Silvia

AU - Torselli, Ilaria

AU - Garofalo, Cecilia

AU - Manara, Maria Cristina

AU - Bongiovanni, Lucia

AU - Valenti, Cesare F.

AU - Burocchi, Alessia

AU - Parenza, Mariella

AU - Cappetti, Barbara

AU - Sangaletti, Sabina

AU - Tripodo, Claudio

AU - Scotlandi, Katia

AU - Colombo, Mario P.

AU - Chiodoni, Claudia

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer. Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression. Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors.

AB - Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer. Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression. Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors.

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