Early phase trials targeting the T-cell inhibitory molecule PD-L1 have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple negative breast cancer (TNBC) and to investigate PTEN loss as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC(n=120) compared to non-TNBC(n=716) (P<0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression which was present in 20 (19%) of 105 TNBC specimens. PD-L1+ tumors had greater CD8+ T-cell infiltrate than PD-L1- tumors (688 cells/mm versus 263 cells/mm; P<.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN shRNA. PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, PI3K pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Co-culture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBC, suggesting PD-L1 as a therapeutic target in TNBC. Since PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may work to increase anti-tumor adaptive immune responses.
- Received August 19, 2013.
- Revision received December 6, 2013.
- Accepted December 31, 2013.
- Copyright © 2014, American Association for Cancer Research.