MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer

Takahiro Maeda, Masayuki Hiraki, Caining Jin, Hasan Rajabi, Ashujit Tagde, Maroof Alam, Audrey Bouillez, Xiufeng Hu, Yozo Suzuki, Masaaki Miyo, Tsuyoshi Hata, Kunihiko Hinohara, Donald Kufe

Research output: Contribution to journalArticle

19 Citations (Scopus)

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-kB p65 to the PD-L1 promoter. In an immunocom-petent 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 CD8þ 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.

Original languageEnglish
Pages (from-to)205-215
Number of pages11
JournalCancer Research
Volume78
Issue number1
DOIs
Publication statusPublished - Jan 1 2018
Externally publishedYes

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Triple Negative Breast Neoplasms
Immune Evasion
Mucins
NF-kappa B
Transgenic Mice
Neoplasms
Up-Regulation
Down-Regulation
Pharmacology
Breast Neoplasms
Ligands
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Maeda, T., Hiraki, M., Jin, C., Rajabi, H., Tagde, A., Alam, M., ... Kufe, D. (2018). MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. Cancer Research, 78(1), 205-215. https://doi.org/10.1158/0008-5472.CAN-17-1636

MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. / Maeda, Takahiro; Hiraki, Masayuki; Jin, Caining; Rajabi, Hasan; Tagde, Ashujit; Alam, Maroof; Bouillez, Audrey; Hu, Xiufeng; Suzuki, Yozo; Miyo, Masaaki; Hata, Tsuyoshi; Hinohara, Kunihiko; Kufe, Donald.

In: Cancer Research, Vol. 78, No. 1, 01.01.2018, p. 205-215.

Research output: Contribution to journalArticle

Maeda, T, Hiraki, M, Jin, C, Rajabi, H, Tagde, A, Alam, M, Bouillez, A, Hu, X, Suzuki, Y, Miyo, M, Hata, T, Hinohara, K & Kufe, D 2018, 'MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer', Cancer Research, vol. 78, no. 1, pp. 205-215. https://doi.org/10.1158/0008-5472.CAN-17-1636
Maeda T, Hiraki M, Jin C, Rajabi H, Tagde A, Alam M et al. MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. Cancer Research. 2018 Jan 1;78(1):205-215. https://doi.org/10.1158/0008-5472.CAN-17-1636
Maeda, Takahiro ; Hiraki, Masayuki ; Jin, Caining ; Rajabi, Hasan ; Tagde, Ashujit ; Alam, Maroof ; Bouillez, Audrey ; Hu, Xiufeng ; Suzuki, Yozo ; Miyo, Masaaki ; Hata, Tsuyoshi ; Hinohara, Kunihiko ; Kufe, Donald. / MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. In: Cancer Research. 2018 ; Vol. 78, No. 1. pp. 205-215.
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