Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages

J Immunol. 2018 Jan 15;200(2):857-868. doi: 10.4049/jimmunol.1700609. Epub 2017 Dec 11.

Abstract

The enzyme 5-lipoxygenase (5-LO) is key in the synthesis of leukotrienes, which are potent proinflammatory lipid mediators involved in chronic inflammatory diseases including cancer. 5-LO is expressed in immune cells but also found in cancer cells. Although the role of 5-LO in tumor cells is beginning to emerge, with the notion that tumor-promoting functions are attributed to its products, the function of 5-LO in the tumor microenvironment remains unclear. To understand the role of 5-LO and its products in the tumor microenvironment, we analyzed its expression and function in tumor-associated macrophages (TAMs). TAMs were generated by coculturing primary human macrophages (MΦ) with human MCF-7 breast carcinoma cells, which caused cell death of cancer cells followed by phagocytosis of cell debris by MΦ. Expression and activity of 5-LO in TAMs were reduced upon coculture with cancer cells. Downregulation of 5-LO in TAMs required tumor cell death and the direct contact between MΦ and dying cancer cells via Mer tyrosine kinase. Subsequently, upregulation of proto-oncogene c-Myb in TAMs induced a stable transcriptional repression of 5-LO. Reduced 5-LO expression in TAMs was mechanistically coupled to an attenuated T cell recruitment. In primary TAMs from human and murine breast tumors, 5-LO expression was absent or low when compared with monocyte-derived MΦ. Our data reveal that 5-LO, which is required for leukotriene production and subsequent T cell recruitment, is downregulated in TAMs through Mer tyrosine kinase-dependent recognition of apoptotic cancer cells. Mechanistically, we noticed transcriptional repression of 5-LO by proto-oncogene c-Myb and conclude that loss of stromal 5-LO expression favors tumor progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cells, Cultured
  • Chemotaxis, Leukocyte / immunology
  • Enzyme Activation
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Proto-Oncogene Proteins c-myb / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transcription, Genetic

Substances

  • Proto-Oncogene Proteins c-myb
  • Arachidonate 5-Lipoxygenase