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Originally published online as doi:10.1189/jlb.1107729 on June 19, 2008

Published online before print June 19, 2008
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(Journal of Leukocyte Biology. 2008;84:679-688.)
© 2008 by Society for Leukocyte Biology

Skewing the Th cell phenotype toward Th1 alters the maturation of tumor-infiltrating mononuclear phagocytes

Kenichi Nonaka*,{dagger},1, Masanao Saio{dagger},1,2, Tatsuhiko Suwa{dagger}, Alan B. Frey{ddagger}, Naoki Umemura{dagger},§, Hisashi Imai*, Guan-Feng Ouyang{dagger}, Shinji Osada*, Margit Balazs||, Roza Adany||, Yoshihiro Kawaguchi*, Kazuhiro Yoshida* and Tsuyoshi Takami{dagger}

* Departments of Surgical Oncology,
{dagger} Imunopathology, and
§ Oral and Maxillofacial Sciences, Gifu University Graduate School of Medicine, Gifu, Japan;
{ddagger} Department of Cell Biology, New York University School of Medicine, New York, New York, USA; and
|| Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary

2 Correspondence: Department of Immunopathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan. E-mail: saio{at}gifu-u.ac.jp

ABSTRACT

Mononuclear phagocytes (MPCs) at the tumor site can be divided into subclasses, including monocyte-lineage myeloid-derived suppressor cells (MDSCs) and the immunosuppressive tumor-infiltrating macrophages (TIMs). Cancer growth coincides with the expansion of MDSCs found in the blood, secondary lymphoid organs, and tumor tissue. These MDSCs are thought to mature into macrophages and to promote tumor development by a combination of growth-enhancing properties and suppression of local antitumor immunoresponses. As little is known about either subset of MPCs, we investigated MPCs infiltrating into murine adenocarcinoma MCA38 tumors. We found that these MPCs displayed immunosuppressive characteristics and a MDSC cell-surface phenotype. Over 70% of the MPCs were mature (F4/80+Ly6C–) macrophages, and the rest were immature (F480+ Ly6C+) monocytes. MPC maturation was inhibited when the cells infiltrated a tumor variant expressing IL-2 and soluble TNF type II receptor (sTNFRII). In addition, the IL-2/sTNFRII MCA38 tumor microenvironment altered the MPC phenotype; these cells did not survive culturing in vitro as a result of Fas-mediated apoptosis and negligible M-CSFR expression. Furthermore, CD4+ tumor-infiltrating lymphocytes (TILs) in wild-type tumors robustly expressed IL-13, IFN-{gamma}, and GM-CSF, and CD4+ TILs in IL-2/sTNFRII-expressing tumors expressed little IL-13. These data suggest that immunotherapy-altered Th cell balance in the tumor microenvironment can affect the differentiation and maturation of MPCs in vivo. Furthermore, as neither the designation MDSC nor TIM can sufficiently describe the status of monocytes/macrophages in this tumor microenvironment, we believe these cells are best designated as MPCs.

Key Words: cancer • tumor necrosis factor • interleukin-2 • interleukin-13 • granulocyte macrophage-colony stimulating factor