Poh, Tze Wei

Abstract Purpose: MUC1 is a tumor-associated antigen that is aberrantly expressed in cancer and inflammatory bowel disease (IBD). Even though immune cells express low MUC1 levels, their modulations of MUC1 are important in tumor progression. Consistent with previous clinical data that show increased myeloid-derived suppressor cells (MDSCs) in IBD, we now show that downregulation of MUC1 on hematopoietic cells increases MDSCs in IBD, similar to our data in tumor-bearing mice. We hypothesize that MDSC expansion in IBD is critical for tumor progression. Experimental Design: To mechanistically confirm the linkage between Muc1 downregulation and MDSC expansion, we generated chimeric mice that did not express Muc1 in the hematopoietic compartment (KO→WT). These mice were used in two models of colitis and colitis-associated cancer (CAC) and their responses were compared with wild-type (WT) chimeras (WT→WT). Results: KO→WT mice show increased levels of MDSCs during colitis and increased protumorigenic signaling in the colon during CAC, resulting in larger colon tumors. RNA and protein analysis show increased upregulation of metalloproteinases, collagenases, defensins, complements, growth factors, cytokines, and chemokines in KO→WT mice as compared with WT→WT mice. Antibody-mediated depletion of MDSCs in mice during colitis reduced colon tumor formation during CAC. Conclusion: Development of CAC is a serious complication of colitis and our data highlight MDSCs as a targetable link between inflammation and cancer. In addition, the lack of MUC1 expression on MDSCs can be a novel marker for MDSCs, given that MDSCs are still not well characterized in human cancers. Clin Cancer Res; 19(18); 5039–52. ©2013 AACR.

Abstract Allogeneic hematopoietic stem cell (HSC) transplantation is a promising area of therapy for various hematological malignancies like chronic/acute myeloid leukemia, myelodysplasia and lymphomas. Its effectiveness at inducing the graft versus tumor (GVT) effect is however, compromised by the graft versus host disease (GVHD) frequently observed in recipients post transplant. One of the strategies utilized in minimizing the effect of GVHD while still preserving GVT activity has been to target immunosuppressive cell types like Treg cells or myeloid derived suppressor cells (MDSCs), in an attempt to correct the balance between GVHD and GVT. MDSCs have been shown to be able to inhibit GVHD but not much is known about the ability of MDSCs to preserve GVT. We have previously shown that myeloid progenitors lacking Muc1 from Muc1 knockout (KO) C57BL/6 (H-2b) mice generate more effective MDSCs in vitro and in vivo. In this current study, we study the potential of using MDSCs generated in the absence of Muc1 to alleviate T cell expansion while preserving CTL activity. Our preliminary data shows that MDSCs generated from Muc1 KO C57BL/6 (H-2b) bone marrow are able to inhibit C57BL/6 (H-2b) T cell proliferation in an allogeneic mixed lymphocyte reaction, using Balb/c (H-2d) stimulators, more effectively than wildtype (WT) MDSCs. Interestingly, despite the reduced T cell proliferation in the presence of KO MDSCs, the CTL activity of these C57BL/6 T cells was still preserved, as demonstrated by their ability to lyse Balb/c A-20 leukemia cells. These results inidicate that co transplant of MDSCs generated in the absence of Muc1 can alleviate GVHD across fully mismatched major histocompatibility complex (MHC) barriers while still preserving the GVT ability of the allograft. This would also validate the clinical desirability of down regulating MUC1 in HSCs for more effective generation of MDSCs in a clinical allogeneic HSC transplantation setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1935.

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