CD44 promotes PD-L1 expression and its tumor-intrinsic function in breast and lung cancers.

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 been recently 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. This data provides a novel basis for CD44 as a critical therapeutic target to suppress PD-L1 tumor-intrinsic function.