Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer

Cancer Immunol Immunother. 2014 Mar;63(3):215-24. doi: 10.1007/s00262-013-1503-x. Epub 2013 Dec 3.

Abstract

The programmed death-1 (PD-1) pathway is important in the maintenance of peripheral tolerance and homeostasis through suppression of T cell receptor signaling. As such, it is employed by many tumors as a means of immune escape. We have investigated the role of this pathway in human ovarian cancer (OC) to assess its potential role as a diagnostic and/or prognostic marker and therapeutic target, following recent clinical trial success of antibody therapy directed at this pathway. We show programmed death ligand-1 (PD-L1) expression on monocytes in the ascites and blood of patients with malignant OC is strikingly higher than those with benign/borderline disease, with no overlap in the values between these groups. We characterize the regulation of this molecule and show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T cells present in the ascites and blood showed a correlation of PD-1 expression with malignant tumors versus benign/borderline, in a similar manner to PD-L1 expression on monocytes. Finally, we demonstrate functional links between PD-L1 expression on monocytes and OC tumor cells with suppression of T cell responses. Overall, we present data based on samples obtained from women with ovarian cancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use with PD-1/PD-L1-directed antibody immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Blocking / immunology
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Biomarkers, Tumor / metabolism*
  • Carcinogenesis
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunosuppression
  • Interleukin-10 / immunology
  • Lymphocyte Activation
  • Molecular Targeted Therapy / methods*
  • Monocytes / immunology
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / pathology*
  • Prognosis
  • Programmed Cell Death 1 Receptor / metabolism*
  • T-Lymphocytes / immunology
  • Tumor Escape

Substances

  • Antibodies, Blocking
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interleukin-10