Lack of Muc1-Regulated β-Catenin Stability Results in Aberrant Expansion of CD11b+Gr1+ Myeloid-Derived Suppressor Cells from the Bone Marrow

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that inhibit T-cell activity and contribute to the immune suppression characteristic of most tumors. We discovered that bone marrow (BM) progenitor cells from the Muc1 knockout (KO) mice differentiated into CD11b + Gr1 + MDSCs in vitro under granulocyte macrophage colony-stimulating factor and interleukin-4 signaling. MUC1 is a tumor-associated mucin and its cytoplasmic tail (MUC1-CT) can regulate B-catenin to promote oncogenesis. Given the importance of B-catenin in hematopoiesis, we hypothesized that the MUC1 regulation of B-catenin is important for MDSC development. Our current study shows that the aberrant development of BM progenitors into CD11b + Gr1 + MDSCs is dependent on the down-regulation of B-catenin levels that occurs in the absence of Muc1. In light of this, KO mice showed enhanced EL4 tumor growth and were able to better tolerate allogeneic BM185 tumor growth, with an accumulation of CD11b + Gr1 + cells in the blood and tumor-draining lymph nodes. WT mice were able to similarly tolerate allogeneic tumor growth when they were injected with CD11b + Gr1 + cells from tumor-bearing KO mice, suggesting that tolerance of allogeneic tumors is dependent on MDSCmediated immune suppression. This further delineates the ability of Muc1 to control MDSC development, which could directly affect tumorigenesis. Knowledge of the biology by which Muc1 regulates the development of myeloid progenitors into MDSCs would also be very useful in enhancing the efficacy of cancer vaccines in the face of tumor immune suppression. [Cancer Res 2009;69(8):3554-62]

The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment

“…Our finding that the negative regulation of MDSCs by CUL4B is mediated by b-catenin is consistent with two recent reports of b-catenin being a negative regulator of MDSCs (17,18). We showed that pharmacologic inhibition of GSK3b drastically reduced the growth of tumor grafts in Cul4b CKO mice.…”

“…Many studies indicated that a tight regulation of Wnt signaling is required for normal hematopoiesis and lymphopoiesis (12)(13)(14)(15). b-Catenin was recently shown to negatively regulate the functions of immunosuppressive cells, including regulatory T cell (Treg) and MDSCs (16)(17)(18). However, how Wnt signaling is regulated in those immunosuppressive cells remains to be elucidated.…”

Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice

“…Activation of both EP2 and EP4 heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors could liberate G protein bg subunits and activate the phosphoinositide 3-kinase pathway, which is likely to be a vital signaling event in generation of MDSCs in BM. 38 Moreover, the immunosuppressive function of PMN-MDSCs is dramatically reduced in aspirintreated/COX-1-deficient mice and in patients with AIA, which is also correlated with arginase activity in PMN-MDSCs. Moreover, COX-1 expression was downregulated in nasal/bronchial epithelial cells and fibroblasts from patients with AIA.…”

A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells

“…Adoptive transfer of MDSCs to recipient mice was performed 4 days after inoculation with 4T1 cells, and then given every 7 days thereafter for 3 weeks. Tumors at the site of injection were measured using an electronic calipers and tumor diameters were calculated as the square root of the length × width of the tumor as previously described [16,54]. Mice were sacrificed for endpoint analyses when the diameter of the tumor reached > 20 mm.…”