Tumour-derived GM-CSF promotes granulocyte immunosuppression in mesothelioma patients

Research output: Contribution to journalArticle

Authors

  • Swati Khanna
  • Anish Thomas
  • Neha Wali
  • Bahar Guliz Yenidunya
  • Constance M. Yuan
  • Betsy Morrow
  • Jingli Zhang
  • Firouzeh Korangy
  • Tim F. Greten
  • Seth M. Steinberg
  • Maryalice Stetler-Stevenson
  • Raffit Hassan

External organisations

  • Department of Clinical Immunology, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
  • Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute
  • Developmental Therapeutcs Branch, National Cancer Institute
  • Biological Sciences, University of Maryland
  • KUSOM, Koç University
  • Laboratory of Pathology, Center for Cancer Research, National Cancer Institute
  • Navy Medical Oncology, NCI.
  • National Cancer Institute (NCI)
  • Thoracic and Gastrointestinal Oncology Branch, NIH/NCI.
  • Biostatistics and Data Management Sections, National Cancer Institute
  • Laboratory of Pathology, National Cancer Institute
  • Thoracic and GI Oncology Branch, National Cancer Institute

Abstract

PURPOSE: The cross talk between tumour cells, myeloid cells, and T cells play a critical role in tumour pathogenesis and response to immunotherapies. Although the aetiology of mesothelioma is well understood the impact of mesothelioma on the surrounding immune microenvironment is less well studied. In this study the effect of the mesothelioma microenvironment on circulating and infiltrating granulocytes and T cells is investigated.

EXPERIMENTAL DESIGN: Tumour and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T cell suppression. Co-cultures of granulocytes, mesothelioma cells, T cells were used to identify the mechanism of T cell inhibition.

RESULTS: Analysis of tumours showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T cell proliferation and activation. Characterisation of the blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared to healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of Reactive Oxygen Species (ROS) from granulocytes, resulting in T cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumours express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralising antibody, or ROS inhibition, restored T cell proliferation suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients.

CONCLUSIONS: Our study presents the mechanism behind the cross-talk between mesothelioma and the immune micro-environment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy.

Details

Original languageEnglish
JournalClinical Cancer Research
Early online date30 Mar 2018
Publication statusE-pub ahead of print - 30 Mar 2018

Keywords

  • Journal Article