PD-L1 expression in triple-negative breast cancer.
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.
Authors' Affiliations: Departments of Department of Urology, The Mayo Clinic, Rochester, Minnesota.
Elizabeth A
EA
Mittendorf
Anne V
AV
Philips
Funda
F
Meric-Bernstam
Na
N
Qiao
Yun
Y
Wu
Susan
S
Harrington
Xiaoping
X
Su
Ying
Y
Wang
Ana M
AM
Gonzalez-Angulo
Argun
A
Akcakanat
Akhil
A
Chawla
Michael
M
Curran
Patrick
P
Hwu
Padmanee
P
Sharma
Jennifer K
JK
Litton
Jeffrey J
JJ
Molldrem
Gheath
G
Alatrash
D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D030541:Databases, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism
D060890:B7-H1 Antigen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase