Muc1 regulates MDSC expansion and suppressive activity in healthy and tumor-bearing mice (P2049)

Abstract

Abstract We demonstrate that a membrane-tethered epithelial mucin, Muc1 affects the differentiation of immature myeloid derived cells (IMCs) in the bone marrow (BM). First, in wild-type (WT) mice, BM-derived Lin-Sca1+ hematopoietic progenitor cells (HPCs) express Muc1. Second, in Muc1-/- mice, the percentage of IMCs is higher and these cells express higher levels of c-MYC as compared to IMCs from WT mice. Interestingly, the myeloid derived suppressor cells (MDSCs) in the Muc1-/- tumor-bearing mice are less differentiated and have higher suppressor function as compared to MDSCs from WT mice. Because of the higher suppressive functions of the MDSCs in the Muc1-/- mice, we confirm that subcutaneous tumors develop significantly faster in these mice as compared to the WT mice (Poh 2009). Further, Muc1-/- mice have decreased NK cell function possibly due to increased suppressive function of their MDSCs. Decreased cytotoxic function of NK cells can partially explain the increased susceptibility of Muc1-/- mice to tumor growth. Lastly, we show that MDSCs from Muc1-/- mice have higher levels of phospho-STAT3, which is known to be critical for MDSC expansion. This finding is of great importance since systemic targeting of Muc1 in several carcinomas is being actively explored. It becomes clear that therapeutic targeting of Muc1 must be localized to the epithelial tumors because down-regulating Muc1 expression in hematopoietic progenitor cells may lead to increased MDSCs.