Macrophage Colony-Stimulating Factor mediates its Immunosuppressive Activity through the Emerging Myeloid Cells during Tumor Progression

Mechanisms by which tumors evade immune surveillance remain to be addressed. In our previous study, we reported that murine mammary tumor (4T1) cells secrete immunosuppressive soluble factor(s), which was identified to be a 10-100 kDa protein. In the current study, we report that analysis of the proteins in the active fractions revealed the presence of macrophage colony-stimulating factor (M-CSF) as one of the suppressive factors secreted by 4T1 tumor cells. Although previously identified as a cytokine that regulates survival, proliferation, and differentiation of macrophages and monocytes, M-CSF has also been associated with tumor progression and metastasis. To date, the immunosuppressive activity of M-CSF is not well understood. To better understand the immunosuppressive activity of M-CSF, we studied the activity of recombinant murine M-CSF in splenocytes isolated from 4T1 tumor-bearing mice. Reduced levels of interferon-gamma (IFN-γ) by M-CSF were observed in a dose-dependent manner indicating suppressive activities of M-CSF on the T-cell activation. M-CSF reduces the secretion of IFN-γ without affecting its intracellular protein expression. The suppressive activity of M-CSF is dependent on the length of days after tumor inoculation as no activity was observed in splenocytes from one-week tumor-bearing mice. This phenomenon correlates with an increase in the number of myeloid cells in the spleen during tumor progression. The suppressive activity of M-CSF is thus thought to be mediated by the myeloid cells emerging during tumor growth.