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

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona

^* To whom correspondence should be addressed. E-mail: gendler.sandra{at}mayo.edu.

	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 -catenin to promote oncogenesis. Given the importance of -catenin in hematopoiesis, we hypothesized that the MUC1 regulation of -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 -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 MDSC-mediated 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]

Key Words: -catenin, Muc1, myeloid-derived suppressor cells