title: Combined Trabectedin and anti-PD1 antibody produces a synergistic antitumor effect in a murine model of ovarian cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gynecology and Obstetrics, Shengjing Hospital, China Medical University, Shenyang, 110004, China. zqg_cmu@163.com.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Acute Abdominal Surgery, The First Hospital of Dalian Medical University, Dalian, 116044, China. zhangxx0591@163.com.
authors.forename: Haolin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Molecular Oncology Department of Cancer Research Institution, The First Hospital of China Medical University, Shenyang, 110004, China. mgfandong@163.com.
authors.forename: Fandong
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Gynecology and Obstetrics, Shengjing Hospital, China Medical University, Shenyang, 110004, China. lijie_cmu@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gynecology and Obstetrics, Shengjing Hospital, China Medical University, Shenyang, 110004, China. sulanzhang_cmu@126.com.
authors.forename: Shulan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D007114:Immunization; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000096:biosynthesis; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D010533:Peritoneal Lavage; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D000077606:Trabectedin; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D004149:Dioxoles; D061026:Programmed Cell Death 1 Receptor; D044005:Tetrahydroisoquinolines; D007371:Interferon-gamma; D000077606:Trabectedin