Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host

TLDR

Accumulation of myeloid suppressor cells (MSCs) in tumor‑bearing mice and cancer patients is linked to immune suppression, with their activity correlating with expression of Gr‑1, CD115, and F4/80 markers. Treg development requires antigen‑associated activation of tumor‑specific T cells, depends on IFN‑γ and IL‑10, and occurs independently of nitric‑oxide–mediated MSC suppression. Gr‑1+CD115+ MSCs suppress T‑cell proliferation, induce anergic Foxp3+ T regulatory cells in vivo, and enhance IL‑10 and TGF‑β secretion upon IFN‑γ stimulation, demonstrating a novel MSC‑mediated immune‑suppressive pathway. Cancer Res 2006; 66(2):1123‑31.

Abstract

Abstract The accumulation of myeloid suppressor cells (MSCs) is associated with immune suppression in tumor-bearing mice and in cancer patients. The suppressive activity of MSC correlates with the expression of the myeloid markers Gr-1, CD115 (macrophage colony-stimulating factor receptor), and F4/80. Gr-1+CD115+ MSCs, in addition to being able to suppress T-cell proliferation in vitro, can induce the development of Foxp3+ T regulatory cells (Treg) in vivo, which are anergic and suppressive. Furthermore, the secretion of interleukin (IL)-10 and transforming growth factor-β by Gr-1+CD115+ MSCs was induced and enhanced, respectively, on IFN-γ stimulation. The development of Treg requires antigen-associated activation of tumor-specific T cells, depends on the presence of IFN-γ and IL-10, and is independent of the nitric oxide–mediated suppressive mechanism by MSC. Our data provide evidence that Gr-1+CD115+ MSC can mediate the development of Treg in tumor-bearing mice and show a novel immune suppressive mechanism by which MSCs can suppress antitumor responses. (Cancer Res 2006; 66(2): 1123-31)