MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer

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 transcription by recruitment of MYC and NF-κB p65 to the 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. 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. .

Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate

“…The MUC1-C oncoprotein is a highly attractive target based on its aberrant overexpression in many types of carcinomas (Supplemental Figure 9). The importance of MUC1-C in driving the epithelial-mesenchymal transition program, the cancer stem cell state, drug resistance, and immune evasion has further emphasized a critical need for developing agents against this target (8,(12)(13)(14)(15). The present results describe the development of an antibody, designated 3D1, which reacts with high affinity to the MUC1-C/ED.…”

“…Of further interest in this regard is the previously unrecognized role for MUC1-C in promoting immune evasion by driving PD-L1 expression and suppressing that of immune effectors, such as IFN-γ, in NSCLC cells (14). As a result, targeting MUC1-C function with the GO-203 inhibitor of the intracellular domain downregulates PD-L1, induces IFN-γ, and enhances effector activity of CD8 + tumor-infiltrating T cells in MUC1.Tg mouse models of NSCLC and TNBC (15,31) and in patients with acute myelogenous leukemia (32). These findings have highlighted the potential for targeting MUC1-Cexpressing cancer cells as an approach for reprogramming of the tumor microenvironment.…”

“…of polarity, the cancer stem cell state, epithelial-mesenchymal transition, and epigenetic programming of cancer cells (8,12). Moreover, MUC1-C integrates the epithelial-mesenchymal transition program with induction of the programmed death ligand 1 (PD-L1) and immune evasion (12)(13)(14)(15). In concert with these findings, overexpression of MUC1-C in breast and lung carcinomas is associated with induction of gene signatures that are predictive of significant decreases in disease-free and overall survival, further supporting the attractiveness of MUC1-C as a cancer target (16)(17)(18).…”

MUC1-C represses the RASSF1A tumor suppressor in human carcinoma cells

“…The asterisk (*) denotes a p-value < 0.05 methylation and inactivation [49]. Of potential relevance to those findings, MUC1-C drives MYC [34,50,51], EZH2 [32], and DNMT3b [30] expression in cancer cells and could thereby contribute to the formation of MYC/EZH2/ DNMT3b complexes. MUC1-C also activates the inflammatory NF-κB p65 pathway, binds to NF-κB p65 and induces transcription of ZEB1 [38,41,52] (Fig.…”

“…Of additional importance, RAS signaling in cancer is MYC dependent [57,61]. In this respect, MUC1-C drives MYC expression in carcinoma cells [34,50,51] and, accordingly, targeting MUC1-C could suppress integration of the RAS and MYC pathways in promoting cancer progression.…”