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Cited by 1,396

The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.

PD-L1 Expression in Triple-Negative Breast Cancer

Open access
Mittendorf, Elizabeth A., Philips, Anne V., Meric-Bernstam, Funda, Qiao, Na, Wu, Yun, Harrington, Susan, Su, Xiaoping, Wang, Ying, Gonzalez-Angulo, Ana M., Akcakanat, Argun, Chawla, Akhil, Curran, Michael, Hwu, Patrick, Sharma, Padmanee, Litton, Jennifer K., Molldrem, Jeffrey J., Alatrash, Gheath·2014·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-13-0127
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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. Cancer Immunol Res; 2(4); 361–70. ©2014 AACR.

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Metadata

Authors
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.
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-04-01
Volume
2
Issue
4
Pages
361-370
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-13-0127
OpenAlex
W2100413206
Cited by
1,396
References
12
FWCI
29.30
Type
journal article
Language
en
Open access
bronze

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