1. Combined Trabectedin and anti-PD1 antibody produces a synergistic antitumor effect in a murine model of ovarian cancer
- Author
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Zhiqiang Guo, Haolin Wang, Shulan Zhang, Jie Li, and Fandong Meng
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,Antibodies, Neoplasm ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Dioxoles ,Pharmacology ,CD8-Positive T-Lymphocytes ,General Biochemistry, Genetics and Molecular Biology ,Interferon-gamma ,Immune system ,Antigen ,Cancer immunotherapy ,Antigens, Neoplasm ,Cell Line, Tumor ,Tetrahydroisoquinolines ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Tumor Microenvironment ,Animals ,Peritoneal Lavage ,Trabectedin ,Medicine(all) ,Immunosuppression Therapy ,Ovarian Neoplasms ,Tumor microenvironment ,business.industry ,Biochemistry, Genetics and Molecular Biology(all) ,Research ,Drug Synergism ,General Medicine ,medicine.disease ,Tumor antigen ,Mice, Inbred C57BL ,Disease Models, Animal ,Cytokine secretion ,Female ,Immunization ,business ,Ovarian cancer ,medicine.drug - Abstract
Background Monoclonal antibodies (mAb) that block programmed death (PD)-1 signaling pathway hold great potential as a novel cancer immunotherapy. Recent evidence suggests that combining with conventional, targeted or other immunotherapies, these mAb can induce synergistic antitumor responses. In this study, we investigated whether Trabectedin (ET-743), a novel anticancer agent currently used for treating relapsed ovarian cancer, can synergize with anti (α)-PD-1 mAb to increase antitumor activity in the murine ID8 ovarian cancer model. Methods Mice with established peritoneal ID8 tumor were treated with either single or combined Trabectedin and α-PD-1 mAb, their overall survival was recorded; tumor-associated immune cells and immune gene expression in tumors from treated mice were analyzed by flow cytometry and quantitative RT-PCR, respectively, and antigen-specific immunity of effector CD8+ T cells was evaluated by ELISA and cytotoxicity assay. In addition, the effect of Trabectedin on tumoral PD-L1 expression was analyzed by both flow cytometry and immunofluorescence staining. Results Though single treatment showed a modest antitumor effect in mice bearing 10-day-established ID8 tumor, combined Trabectedin and α-PD-1 mAb treatment induced a strong antitumor immune response, leading to a significant tumor regression with half of mice tumor-free 90 days after tumor inoculation. Mechanistic investigation revealed that combination treatment induces a systemic tumor-specific immunity with an indispensable role of both CD4+ and CD8+ T cells, and effector CD8+ T cells exhibited the antigen-specific cytokine secretion and cytotoxicity upon tumor antigen stimulation; additionally, combination treatment increased the IFN-γ-producing effector T cells and decreased the immunosuppressive cells in peritoneal cavity; accordingly, it enhanced the expression of Th1-associated immune-stimulating genes while reducing the transcription of regulatory/suppressive immune genes, reshaping tumor microenvironment from a immunosuppressive to a stimulatory state. Finally, in vivo Trabectedin treatment has been shown to induce IFN-γ-dependent PD-L1 expression within tumor, possibly constituting a mechanistic basis for its synergistic antitumor effect with α-PD-1 mAb therapy. Conclusion This study provides the evidence that α-PD-1 mAb can produce a synergistic antitumor efficacy when combined with Trabectedin, a clinically available anticancer agent, supporting a direct translation of this combination strategy in clinic for the treatment of ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0613-y) contains supplementary material, which is available to authorized users.
- Published
- 2015