Format

Send to

Choose Destination
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.

Author information

1
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
2
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
3
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.
4
Department of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
5
Department of Pathology, Glen Site, McGill University Health Centre Montreal, Quebec, Canada.
6
Department of Medicine, Division of Respiratory Medicine, McGill University Health Centre, Montreal Chest Institute, Montreal, Quebec, Canada.
7
Departments of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, Quebec, Canada.
8
Department of Biochemistry, McGill University, Montreal, Quebec, Canada. sidong.huang@mcgill.ca giuseppina.ursini-siegel@mcgill.ca.
9
Department of Oncology, McGill University, Montréal, Quebec, Canada.

Abstract

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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center