GENUS ONCOLOGY - THE MUC1-C COMPANY
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Publication Category:
Role of MUC1-C in Immune Evasion

​(chronological order)
MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer
Cancer Research , 2017; 78(1):205-215; Maeda T, Hiraki M, Jin C, Rajabi H, Tagde A, Alam M, Bouillez A, Hu X, Suzuki Y, Miyo M, Hinohara K, and Kufe D.

click to see abstract

The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 205-15. ©2017 AACR.


MUC1-C promotes the suppressive immune microenvironment in non-small cell lung cancer
OncoImmunology , 2017; 6(9):e1338998; Bouillez A, Adeegbe D, Jin C, Hu X, Tagde A, Alam M, Rajabi H, Wong KK, and Kufe D.

click to see abstract

The cancer immune microenvironment is of importance for the effectiveness of immunotherapy; however, its dysregulation is poorly understood. The MUC1-C oncoprotein is aberrantly overexpressed in non-small cell lung cancer (NSCLC) and has been linked to the induction of PD-L1. The present work investigated the effects of targeting MUC1-C in an immuno-competent MUC1 transgenic (MUC1.Tg) mouse model. We show that Lewis Lung Carcinoma cells expressing MUC1-C (LLC/MUC1) exhibit upregulation of PD-L1 and suppression of interferon-gamma (IFN-gamma). In studies of LLC/MUC1 cells growing in vitro and as tumors in MUC1.Tg mice, treatment with the MUC1-C inhibitor, GO-203, was associated with the downregulation of PD-L1 and induction of IFN-gamma. The results further demonstrate that targeting MUC1-C results in enhanced effector function of CD8+ tumor-infiltrating lymphocytes (TILs) as evidenced by increased expression of the activation marker CD69, the degranulation marker CD107alpha, and granzyme B. Notably, targeting MUC1-C was also associated with marked increases in TIL-mediated killing of LLC/MUC1 cells. Analysis of gene expression data sets further showed that overexpression of MUC1 in NSCLCs correlates negatively with CD8, IFNG and GZMB, and that decreases in CD8 and IFNG are associated with poor clinical outcomes. These findings in LLC/MUC1 tumors and in NSCLCs indicate that MUC1-C-->PD-L1 signaling promotes the suppression of CD8+ T-cell activation and that MUC1-C is a potential target for reprogramming of the tumor microenvironment.


MUC1 inhibition leads to decrease in PD-L1 levels via up-regulation of miRNAs
Leukemia ; [Epub ahead of print](Pyzer AR, Stroopinsky D, Rosenblatt J, Anastasiadou E, Rajabi H, Washington A, Tagde A, Chu JH, Coll M, Jiao AL, Tsai LT, Tenen DE, Cole L, Palmer K, Ephraim A, Leaf RK, Nahas M, Apel A, Zommer MN, Jain S, McMasters M, Mendez L, Arnason J, Raby BA, Slack F, Kufe D, and Avigan D.

click to see abstract

The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in AML, but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA processing. MUC1 signaling decreased the expression of the microRNA processing protein DICER, via the suppression of c-Jun activity. NanoString array of MUC1 silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T cell mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.Leukemia accepted article preview online, 30 May 2017. doi:10.1038/leu.2017.163.


MUC1-C Oncoprotein Integrates a Program of EMT + Epigenetic Reprogramming and Immune Evasion in Human Carcinomas
Biochim Biophys Acta , 2017; 1868(1):117-122; Rajabi H, and Kufe D.

click to see abstract

The MUC1 gene evolved in mammalian species to provide protection of epithelia. The transmembrane MUC1 C-terminal subunit (MUC1-C) signals stress to the interior of the epithelial cell and, when overexpressed as in most carcinomas, functions as an oncoprotein. MUC1-C induces the epithelial-mesenchymal transition (EMT) by activating the inflammatory NF-κB p65 pathway and, in turn, the EMT-transcriptional repressor ZEB1. Emerging evidence has indicated that MUC1-C drives a program integrating the induction of EMT with activation of stem cell traits, epigenetic reprogramming and immune evasion. This mini-review focuses on the potential importance of this MUC1-C program in cancer progression. KEYWORDS: BMI1; DNMTs; EMT; MUC1-C; PD-L1; epigenetics; immune evasion; tumor suppressor genes


MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia
Blood ; 129(13):1791-1801; Pyzer AR, Stroopinsky D, Rajabi H, Washington A, Tagde A, Coll M, Fung J, Bryant MP, Cole L, Palmer K, Somaiya P, Leaf RK, Nahas M, Apel A, Jain S, McMasters M, Mendez L, Levine J, Joyce R, Arnason J, Pandolfi PP, Kufe D, Rosenblatt J, and Avigan D.

click to see abstract

Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in Acute Myeloid Leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, compared to normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b+ Gr1+ MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-14, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact dependent expansion of MDSCs. MDSCs were suppressive of autologous T cell responses as evidenced by reduced T cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived Extracellular Vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken up myeloid progenitor cells resulting in the selective proliferation of MDSCs as compared to functionally competent antigen presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.


MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small cell lung cancer
Oncogene , Jan 2017; 36:4037-4046; Bouillez A, Rajabi H, Jin C, Samur M, Tagde A, Alam M, Hiraki M, Maeda T, Hu X, Adeegbe D, Kharbanda S, Wong K-K and Kufe D.

click to see abstract

Immunotherapeutic approaches, particularly programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade, have improved the treatment of non-small-cell lung cancer (NSCLC), supporting the premise that evasion of immune destruction is of importance for NSCLC progression. However, the signals responsible for upregulation of PD-L1 in NSCLC cells and whether they are integrated with the regulation of other immune-related genes are not known. Mucin 1 (MUC1) is aberrantly overexpressed in NSCLC, activates the nuclear factor-κB (NF-κB) p65→︀ZEB1 pathway and confers a poor prognosis. The present studies demonstrate that MUC1-C activates PD-L1 expression in NSCLC cells. We show that MUC1-C increases NF-κB p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription. Moreover, we demonstrate that MUC1-C-induced activation of NF-κB→︀ZEB1 signaling represses the TLR9 (toll-like receptor 9), IFNG, MCP-1 (monocyte chemoattractant protein-1) and GM-CSF genes, and that this signature is associated with decreases in overall survival. In concert with these results, targeting MUC1-C in NSCLC tumors suppresses PD-L1 and induces these effectors of innate and adaptive immunity. These findings support a previously unrecognized central role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.


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  • Company
    • Mission
    • About Us
    • Genus Overview
    • Management
    • Board of Directors
    • Scientific Advisory Board
    • Clinical and Research Partners
    • Contact
    • Sitemap
  • Why Target MUC1-C?
  • Clinical Trials
    • Summary
    • GO-203
    • Phase 2 AML Clinical Trial
  • The Science
    • Overview
    • MUC1 in Human Cancer: The Numbers
    • MUC1 in Human Cancer: Overexpression
    • Target for Carcinoma Stem-Like Cell
    • Target for Leukemia Stem Cell
    • MUC1-C is an Attractive Target for Reversing Immune Evasion
    • Intellectual Property
  • Programs
    • Pipeline
    • Targeting the Cytoplasmic Domain
    • Targeting the Extracellular Domain
    • Biomarker Program
  • News & Publications
    • News
    • Publications >
      • Complete Listing
      • Role of MUC1-C in Signal Transduction
      • Role of MUC1-C in Epigenetic Regulation
      • Role of MUC1-C in Immune Evasion
      • MUC1 Vaccine
      • MUC1-C in Stem-like Cells
      • MUC1-C inhibitor formulated in Nanoparticles
      • MUC1-C inhibitor is synergistic with chemotherapeutic and targeted drugs
      • MUC1-C is a druggable target