Published online before print December 30, 2009

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0909607

Received for publication September 9, 2009.
Revised November 20, 2009.
Accepted for publication November 23, 2009.

Article

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 , and George Miller ^*@

*S. Arthur Localio Laboratory, Department of Surgery, and Departments ofBiochemisry andCell Biology, New York University School of Medicine, New York, New York, USA

^@ To whom correspondence should be addressed. E-mail: george.miller{at}nyumc.org.

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.

Key Words: T cells • MDSC • cancer • hepatic • immune suppression