PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer

PLoS One. 2014 Feb 27;9(2):e89350. doi: 10.1371/journal.pone.0089350. eCollection 2014.

Abstract

The co-inhibitory receptor Programmed Death-1 (PD-1) curtails immune responses and prevent autoimmunity, however, tumors exploit this pathway to escape from immune destruction. The co-stimulatory receptor OX40 is upregulated on T cells following activation and increases their clonal expansion, survival and cytokine production when engaged. Although antagonistic anti-PD-1 or agonistic anti-OX40 antibodies can promote the rejection of several murine tumors, some poorly immunogenic tumors were refractory to this treatment. In the present study, we evaluated the antitumor effects and mechanisms of combinatorial PD-1 blockade and OX40 triggering in a murine ID8 ovarian cancer model. Although individual anti-PD-1 or OX40 mAb treatment was ineffective in tumor protection against 10-day established ID8 tumor, combined anti-PD-1/OX40 mAb treatment markedly inhibited tumor outgrowth with 60% of mice tumor free 90 days after tumor inoculation. Tumor protection was associated with a systemic immune response with memory and antigen specificity and required CD4(+) cells and CD8(+) T cells. The anti-PD-1/OX40 mAb treatment increased CD4(+) and CD8(+) cells and decreased immunosuppressive CD4(+)FoxP3(+) regulatory T (Treg) cells and CD11b(+)Gr-1(+) myeloid suppressor cells (MDSC), giving rise to significantly higher ratios of both effector CD4(+) and CD8(+) cells to Treg and MDSC in peritoneal cavity; Quantitative RT-PCR data further demonstrated the induction of a local immunostimulatory milieu by anti-PD-1/OX40 mAb treatment. The splenic CD8(+) T cells from combined mAb treated mice produced high levels of IFN-γ upon tumor antigen stimulation and exhibited antigen-specific cytolytic activity. To our knowledge, this is the first study testing the antitumor effects of combined anti-PD-1/OX40 mAb in a murine ovarian cancer model, and our results provide a rationale for clinical trials evaluating ovarian cancer immunotherapy using this combination of mAb.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Neoplasm / immunology
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / drug effects
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte
  • Female
  • Immunotherapy
  • Mice
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, OX40 / agonists*
  • Receptors, OX40 / metabolism
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Burden
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Epitopes, T-Lymphocyte
  • Programmed Cell Death 1 Receptor
  • Receptors, OX40

Grant support

This work was supported by the Free Researcher Project of Shengjing Hospital (No.200806). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.