GENUS ONCOLOGY - THE MUC1-C COMPANY
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MUC1-C is an Attractive Target for Reversing Immune Evasion​

Importance to immune-mediated approaches, such as ADCs, ADCCs, BsAbs, and CAR-Ts, against MUC1-expressing tumors.
Targeting MUC1-C reverses immune evasion in TNBC (1).

PD-L1 is upregulated in TNBC and is of importance to the pathogenesis of this cancer. Our studies show that MUC1-C upregulates PD-L1 in human TNBC cells.  We found that targeting MUC1-C with genetic approaches or pharmacologic inhibition suppresses PD-L1 expression.  MUC1-C promotes MYC and NF-B p65 occupancy on the PD-L1 promoter and thereby drives PD-L1 transcription.  Overexpression of MUC1-C in mouse Eo771 TNBC cells was similarly associated with induction of PD-L1 expression and provided a model for studies in immune competent MUC1 transgenic (MUC1.Tg) mice.  Targeting MUC1-C in Eo771/MUC1-C tumors growing in MUC1.Tg mice resulted in the downregulation of PD-L1 expression.  Suppression of PD-L1 was also associated with activation of tumor infiltrating CD8+ T cells as evidenced by increases in CD69, granzyme B and killing of Eo771/MUC1-C cells.  Analysis of TNBC datasets further showed that (i) MUC1 expression correlates negatively with that of CD8, CD69 and GZMB and (ii) downregulation of CD8, CD69 and GZMB expression is associated with decreases in patient survival.
​
These findings in immunocompetent NSCLC and TNBC tumor models (1-3) provide previously unrecognized insights into the involvement of MUC1-C in a program of immune evasion that has the potential for broad applicability to other types of cancer.  The findings also support the targeting of MUC1-C as a potential immunotherapeutic approach for the treatment of patients with these cancers.

MUC1-C is a target for reversing immune evasion in NSCLC (3). 

The effects of targeting MUC1-C have also been investigated in an immuno-competent MUC1 transgenic (MUC1.Tg) mouse model of NSCLC. Treatment with the MUC1-C inhibitor, GO-203, was associated with the downregulation of PD-L1 and induction of IFN-.  In addition, targeting MUC1-C resulted in enhanced activation and effector function of CD8+ tumor-infiltrating lymphocytes (TILs) as evidenced by increased expression of the activation marker CD69, the degranulation marker CD107 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 datasets 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-CPD-L1 signaling promotes the suppression of CD8+ T cell activation and that MUC1-C activity extends beyond tumor cell-intrinsic oncogenic functions to regulate suppressive features of tumor-associated immune cells. Thus, MUC1-C is a potential target for reprogramming of the tumor microenvironment to promote anti-tumor immunity.

MUC1-C induces PD-L1 and a program of immune evasion (2).

PD-1/PD-L1 blockade has improved the treatment of NSCLC, indicating 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.  MUC1-C is aberrantly overexpressed in NSCLC, activates the NF-B p65ZEB1 pathway and confers a poor prognosis.  MUC1-C also activates PD-L1 expression in NSCLC cells. MUC1-C increases NF-B p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription (Fig. 1).  Moreover, MUC1-C-induced activation of NF-BZEB1 signaling represses the TLR9, IFNG, MCP-1 and GM-CSF genes, and 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 role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.
Picture
Figure 1.  MUC1-C activates the inflammatory NF-κB p65 pathway and a program of immune evasion.
​

MUC1-C forms a complex with NF-κB p65 and induces the activation of NF-κB target genes, including MUC1 itself, in an autoinductive circuit.  MUC1-C also promotes occupancy of NF-κB p65 on the ZEB1, TLR7 and CD274/PD-L1 promoters and contributes to activation of these genes.  The upregulation of ZEB1 and the formation of MUC1-C/ZEB1 complexes suppresses miR-200c and thereby induces EMT.  MUC1-C/ZEB1 complexes also play a role in suppression of TLR9, IFNG, MCP-1 and GM-CSF, linking these pathways with immune evasion. Thus, targeting MUC1-C suppresses PD-L1 and induces TLR9, IFN-γ, MCP-1 and GM-CSF expression in NSCLC and TNBC tumors, supporting the premise that MUC1-C is of importance for integrating the regulation of these genes.
​MUC1 resides in an immune privileged site on normal epithelial cells.   Evidence that MUC1 expression at the apical borders of normal epithelial cells is NOT targeted by the immune system. 

Reversal of tolerance to MUC1 with induction of anti-tumor activity, but the absence of autoimmunity.   MUC1 transgenic (MUC1.Tg) mice provide a potential model to assess the induction of anti-MUC1 immune responses. In this regard, MUC1-Tg mice express MUC1 in a pattern and at a level similar to that found in man (4). Moreover, the MUC1.Tg mice are tolerant to stimulation by MUC1 antigen (4) or irradiated MUC1-positive carcinoma cells (5).

Other vaccine approaches, such as fusions of carcinoma and dendritic cells, have demonstrated reversal of tolerance to MUC1 in MUC1.Tg mice (5). In this way, fusions of dendritic cells (DC) with MUC1-positive tumor cells induced humoral and cytotoxic T cell activity against MUC1 and resulted in the rejection of established metastatic MUC1-positive tumors (5). Importantly, reversal of tolerance and induction of anti-tumor activity were NOT associated with autoimmunity against MUC1 expressing normal tissues (5).

Other studies with DC-based vaccines directed against MUC1 have similarly demonstrated induction of anti-MUC1 activity against MUC1-positive tumors, but not against MUC1-expressing normal tissues (6-10).

Another vaccine approach against MUC1 has involved the immunization of MUC1.Tg mice with anti-CD19-MUC1 conjugates (11). Here, targeting MUC1 to B cells reversed tolerance to MUC1 and induced humoral and cytotoxic T cell responses that were effective against MUC1-positive tumors (11).  Significantly and as shown for vaccination with DC-based approaches, there were no signs of autoimmunity in MUC1-expressing tissues, including lung, pancreas, liver and mammary duct (11).  These findings provided further support that MUC1-specific immune responses do not cause autoimmune damage to normal MUC1-expressing tissues.

Is expression of MUC1 on the apical borders of normal epithelial cells in an “immune privileged site”?   The apical borders of normal epithelial cells face the external environment in the respiratory and gastrointestinal tracts, and in the ducts of specialized organs. As such, the apical border that is protected by the mucins may represent a unique immune privileged site that limits the induction of immunity against foreign antigens.

In support of this notion is the above evidence that reversal of tolerance to MUC1 in the MUC1.Tg mouse is not associated with autoimmunity against normal epithelia that have restricted MUC1 expression at the apical borders. By contrast, induction of humoral and cytotoxic T cell immunity against MUC1 is highly effective against cancer cells that have lost apical-basal polarity and express MUC1 over the entire cell surface. 

​These findings collectively indicate that MUC1 is in an immune privileged site on the apical borders of normal epithelia. The findings also indicate that immune-mediated therapeutic approaches against MUC1-C-expressing tumors, such as ADC, ADCC, BsAb and CAR-T cells among others, may have highly favorable toxicity profiles because of MUC1 restriction at the apical borders of normal tissues.

​References

  1. 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, MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. Cancer Research, 2017. 78:205-15.
  2. 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, MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small cell lung cancer. Oncogene, 2017. 36:4037-46.
  3. Bouillez A, Adeegbe D, Jin C, Hu X, Tagde A, Alam M, Rajabi H, Wong KK, and Kufe D, MUC1-C promotes the suppressive immune microenvironment in non-small cell lung cancer. OncoImmunology, 2017. 6:e1338998.
  4. Rowse GJ, Tempero RM, VanLith ML, Hollingsworth MA, and Gendler SJ, Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model. Cancer Res, 1998. 58:315-21.
  5. Gong J, Avigan D, and Kufe D, Dendritic-tumor cell fusions. In: Lotze M and Thomson A, eds. Dendritic Cells: Biology and Clinical Applications. Academic Press, 1998.
  6. Chen D, Xia J, Tanaka Y, Chen H, Koido S, Wernet O, Mukherjee P, Gendler SJ, Kufe D, and Gong J, Immunotherapy of spontaneous mammary carcinoma with fusions of dendritic cells and mucin 1-positive carcinoma cells. Immunology, 2003. 109:300-7.
  7. Koido S, Tanaka Y, Chen D, Kufe D, and Gong J, The kinetics of in vivo priming of CD4 and CD8 T cells by dendritic/tumor fusion cells in MUC1-transgenic mice. J Immunol, 2002. 168:2111-7.
  8. Tanaka Y, Koido S, Chen D, Gendler S, Kufe D, and Gong J, Vaccination with allogeneic dendritic cells fused to carcinoma cells induces antitumor immunity in MUC1 transgenic mice. Clin Immunol, 2001. 101:192-200.
  9. Gong J, Apostolopoulos V, Chen D, Chen H, Koido S, Gendler S, McKenzie I, and Kufe D, Selection and characterization of MUC1-specific CD8+ T cells from MUC1 transgenic mice immunized with denritic-carcinoma fusion cells. Immunology, 2000. 101:316-24.
  10. Koido S, Kashiwaba M, Chen D, Gendler S, and Kufe D, Induction of antitumor immunity by vaccination of dendritic cells transfected with MUC1 RNA. J Immunol, 2000. 165:5713-9.
  11. Ding C, Wang L, Marroquin J, and Yan J, Targeting of antigens to B cells augments antigen-specific T-cell responses and breaks immune tolerance to tumor-associated antigen MUC1. Blood, 2008. 112:2817-25

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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