Macrophages can recognize and kill tumor cells bearing the membrane isoform of macrophage colony-stimulating factor

Abstract

NBXFO hybridoma cells produced both the membrane and secreted isoforms of macrophage colony-stimulating factor (M-CSF). Murine bone marrow cells stimulated by the secreted form of M-CSF (sM-CSF) became Mac1+, Mac2+, Mac3+, and F4/80+ macrophages that inhibited the growth of NBXFO cells, but not L1210 or P815 tumor cells. In cytotoxicity studies, M- CSF activated macrophages and freshly isolated macrophages killed NBXFO cells in the presence of polymyxin B, eliminating the possibility that contaminating lipopolysaccharide (LPS) was responsible for the delivery of the cytotoxic signal. Retroviral-mediated transfection of T9 glioma cells with the gene for the membrane isoform of M-CSF (mM-CSF), but not for the secreted isoform of M-CSF, transferred the ability of macrophages to kill these transfected T9 cells in a mM-CSF dose- dependent manner. Macrophage-mediated killing of the mM-CSF transfected clone was blocked by using a 100-fold excess of recombinant M-CSF. Catalase, superoxide dismutase, and the nitric oxide inhibitor, N-omega- nitro-arginine methyl ester (NAME), did not effect macrophage cytotoxicity against the mM-CSF transfectant T9 clones. T9 parental cells when cultured in the presence of an equal number of the mM-CSF transfectant cells were not killed, indicating specific target cell cytotoxicity by the macrophages. Electron microscopy showed that macrophages were capable of phagocytosizing mM-CSF bearing T9 tumor cells and NBXFO hybridoma cells; this suggested a possible mechanism of this cytotoxicity. This study indicates that mM-CSF provides the necessary binding and triggering molecules through which macrophages can initiate direct tumor cell cytotoxicity.

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

“…Similarly, CD8 T cell release of IFN-γ through the direct interaction of pSTAT1 with the pro-survival Bcl2a1 gene promoter impairs the suppressive function of MDSCs [90], while, in APCs, IFN-γ increases surface MHC class I and II expression along with other components of the antigen presentation pathway required for effective peptide recognition [54,91]. This extends to MHC class II induction on M1 macrophages, which can trigger IFN-γ release by Th1 cells to further activate macrophages that express abundant antitumor cytokines and factors, such as fas ligand (FASL) and nitric oxide (NO) [18], and directly phagocytose tumor cells [92].…”

Macrophages define the invasive microenvironment in breast cancer

“…Indeed, in normal physiology, macrophages are generally thought of as being involved in immune reactions, where among other things, they are professional APCs and also are involved in cell and pathogen killing. Furthermore, they are quite capable of killing tumor cells and often do so in in vitro assays [26]. Recently, sophisticated microarray-derived gene expression data combined with cell-phenotyping studies in human colon cancer indicated that an immune environment characterized by an adaptive T cell-mediated immune response correlated with good prognosis in patients that had surgical resections, suggesting that in some cases, the immune system is biased toward tumor cell rejection [27,28].…”

Heterogeneous effects of M‐CSF isoforms on the progression of MLL‐AF9 leukemia

“…Furthermore, LAMs were more potent to killed AML cells with high level of mM-CSF by direct phagocytosis, which was also observed in T9 tumor cells. 48 The antitumor effect suggested that enhanced specific phagocytosis mediated by mM-CSF might also partly account for prolonged survival of leukemia mice.…”