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Cancer Res. 2020 Feb 1;80(3):444-457. doi: 10.1158/0008-5472.CAN-19-1108. Epub 2019 Nov 13.

CD44 Promotes PD-L1 Expression and Its Tumor-Intrinsic Function in Breast and Lung Cancers.

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Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.
Department of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
Department of Pathology, Glen Site, McGill University Health Centre Montreal, Quebec, Canada.
Department of Medicine, Division of Respiratory Medicine, McGill University Health Centre, Montreal Chest Institute, Montreal, Quebec, Canada.
Departments of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, Quebec, Canada.
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Department of Oncology, McGill University, Montréal, Quebec, Canada.


The PD-L1 (CD274) immune-checkpoint ligand is often upregulated in cancers to inhibit T cells and elicit immunosuppression. Independent of this activity, PD-L1 has recently been shown to also exert a cancer cell-intrinsic function promoting tumorigenesis. Here, we establish this tumor-intrinsic role of PD-L1 in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Using FACS-assisted shRNA screens, we identified the cell-surface adhesion receptor CD44 as a key positive regulator of PD-L1 expression in these cancers. Mechanistically, CD44 activated PD-L1 transcription in part through its cleaved intracytoplasmic domain (ICD), which bound to a regulatory region of the PD-L1 locus containing a consensus CD44-ICD binding site. Supporting this genetic interaction, CD44 positively correlated with PD-L1 expression at the mRNA and protein levels in primary tumor samples of TNBC and NSCLC patients. These data provide a novel basis for CD44 as a critical therapeutic target to suppress PD-L1 tumor-intrinsic function. SIGNIFICANCE: CD44 is a potential target to suppress PD-L1 function in TNBC. This finding has the potential to open a new area of therapy for TNBC.

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