Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor

Michael K. Connolly, Jon Mallen St Clair, Andrea S. Bedrosian, Ashim Malhotra, Valery Vera, Junaid Ibrahim, Justin Henning, H. Leon Pachter, Dafna Bar-Sagi, Alan B. Frey, George Miller

Research output: Contribution to journalArticle

Abstract

The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of immune-suppressive cells in the liver of tumor-bearing hosts. We found that in mice with intra-abdominal malignancies, two distinct CD11b+Gr1+ populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b+Gr1+ populations in other tissues of tumor-bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b+Gr1 + cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid-derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra-abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics.

Original languageEnglish (US)
Pages (from-to)713-725
Number of pages13
JournalJournal of Leukocyte Biology
Volume87
Issue number4
DOIs
StatePublished - Apr 2010

Keywords

  • Cancer
  • Hepatic
  • Immune suppression
  • MDSC
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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  • Cite this

    Connolly, M. K., Clair, J. M. S., Bedrosian, A. S., Malhotra, A., Vera, V., Ibrahim, J., Henning, J., Leon Pachter, H., Bar-Sagi, D., Frey, A. B., & Miller, G. (2010). Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor. Journal of Leukocyte Biology, 87(4), 713-725. https://doi.org/10.1189/jlb.0909607