Trabectedin Overrides Osteosarcoma Differentiative Block and Reprograms the Tumor Immune Environment Enabling Effective Combination with Immune Checkpoint Inhibitors

• Published in: Clinical cancer research 2017-09, Vol.23 (17), p.5149-5161
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Aberration; Biocompatibility; Blocking; Blocking antibodies; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - immunology; Bone Neoplasms - pathology; Bone tumors; Cancer; Cbfa-1 protein; CD8 antigen; Cell Differentiation - drug effects; Cell Line, Tumor; Cell proliferation; Cellular Reprogramming - drug effects; Cellular Reprogramming - immunology; Core Binding Factor Alpha 1 Subunit - genetics; Differentiation; Dioxoles - administration & dosage; Dioxoles - adverse effects; Effectiveness; Experimental design; Humans; Immune checkpoint inhibitors; Immune system; Immunotherapy; Immunotherapy - methods; Inhibitors; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lungs; Lymphocytes; Lymphocytes T; Metastases; Metastasis; Mimicry; Osteoblastogenesis; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - immunology; Osteosarcoma - pathology; Ovarian cancer; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tetrahydroisoquinolines - administration & dosage; Tetrahydroisoquinolines - adverse effects; Tumor cells; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor Suppressor Protein p53 - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-3186

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. 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. 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. 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. .