MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer

Abstract

Immunotherapeutic approaches, particularly 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 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, IFNG, MCP-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.

MUC1-C Oncoprotein Integrates a Program of EMT, Epigenetic Reprogramming and Immune Evasion in Human Carcinomas

“…Moreover, recent work has shown that MUC1-C is sufficient to induce PD-L1 expression in carcinoma cells by activation of the inflammatory NF-κB p65 pathway [48]. MUC1-C increases NF-κB p65 occupancy on the PD-L1/CD274 promoter and drives CD274 transcription, indicating that MUC1-C contributes to suppression of immune recognition [48] (Fig. 3B).…”

“…MUC1 protects cancer cells from killing by (i) tumor necrosis-related apoptosis-inducing ligand (TRAIL), (ii) Fas ligand and (iii) perforin/granzyme-dependent lysis by cytotoxic T cells [22, 47]. Moreover, recent work has shown that MUC1-C is sufficient to induce PD-L1 expression in carcinoma cells by activation of the inflammatory NF-κB p65 pathway [48]. MUC1-C increases NF-κB p65 occupancy on the PD-L1/CD274 promoter and drives CD274 transcription, indicating that MUC1-C contributes to suppression of immune recognition [48] (Fig.…”

“…3B). Of additional interest, the MUC1-C→NF-κB p65→ZEB1 pathway represses genes, such as IFNG, which are of importance for activating an anti-tumor immune response [48]. Along these lines, targeting MUC1-C with a pharmacologic inhibitor is associated with downregulation of PD-L1 and induction of IFNγ in vitro and in mouse models.…”

Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression

“…Upon the stimuli of proinflammatory cytokines such as TNF-a, NF-kB can be activated by MAP3K7-IKK signaling axis (Taniguchi and Karin, 2018). In addition to regulating canonical pro-survival genes, NF-kB is known to regulate mRNA expression of PD-L1 (also known as CD274) gene in various cancer types (Bouillez et al, 2017;Peng et al, 2015). A recent CRISPR/Cas9based screening identifies the NF-kB pathway as one of the key mechanisms that promote cancer cell escape from immune attack of T cells (Manguso et al, 2017;Pan et al, 2018).…”

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

“…In the NSCLC progression, the signals responsible for the up‐regulation of PD‐L1 involve Mucin 1 (MUC1) that is aberrantly over expressed, activates the nuclear factor‐kB (NFκB) p65–>ZEB1 pathway and confers a poor prognosis . MUC1‐C increases NFκB p65 occupancy on the Pd‐l1 promoter thereby driving Pd‐l1 transcription, in association with the repressions of the TLR9 (toll‐like receptor 9), IFN‐γ, MCP‐1 (monocyte chemoattractant protein‐1) and GM‐CSF gene expressions that constitute a signature of decreased overall survival, suggesting a central role for MUC1‐C in integrating PD‐L1 activation with suppression of immune effectors causing a poor clinical outcome in NSCLC . More recently, other stimulators of PD‐L1 gene expression are emerging.…”