PD-L1 expression in triple-negative breast cancer

Elizabeth A. Mittendorf, Anne V. Philips, Funda Meric-Bernstam, Na Qiao, Yun Wu, Susan Harrington, Xiaoping Su, Ying Wang, Ana M. Gonzalez-Angulo, Argun Akcakanat, Akhil Chawla, Michael Curran, Patrick Hwu, Padmanee Sharma, Jennifer K. Litton, Jeffrey J. Molldrem, Gheath Alatrash

Research output: Contribution to journalArticle

406 Scopus citations

Abstract

Early-phase trials targeting the T-cell inhibitory molecule programmed cell death ligand 1 (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 the loss of PTEN 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 with non-TNBC (n = 716; P < 0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression, which was present in 19% (20 of 105) of TNBC specimens. PD-L1(+) tumors had greater CD8(+) T-cell infiltrate than PD-L1(-) tumors (688 cells/mm vs. 263 cells/mm; P < 0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN short hairpin RNA (shRNA). PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, phosphoinositide 3-kinase (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. Coculture 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 TNBCs, suggesting PD-L1 as a therapeutic target in TNBCs. Because PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses.

Original languageEnglish (US)
Pages (from-to)361-370
Number of pages10
JournalCancer Immunology Research
Volume2
Issue number4
DOIs
StatePublished - Apr 1 2014

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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  • Cite this

    Mittendorf, E. A., Philips, A. V., Meric-Bernstam, F., Qiao, N., Wu, Y., Harrington, S., Su, X., Wang, Y., Gonzalez-Angulo, A. M., Akcakanat, A., Chawla, A., Curran, M., Hwu, P., Sharma, P., Litton, J. K., Molldrem, J. J., & Alatrash, G. (2014). PD-L1 expression in triple-negative breast cancer. Cancer Immunology Research, 2(4), 361-370. https://doi.org/10.1158/2326-6066.CIR-13-0127