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JAK2 and PD-L1 Amplification Enhance the Dynamic Expression of PD-L1 in Triple-negative Breast Cancer.

Abstract：

BACKGROUND:Activation of the JAK/STAT pathway is common in triple-negative breast cancer (TNBC) and affects the expression of genes controlling immune signaling. A subset of TNBC cases will have somatic amplification of chromosome 9p24.1, encoding PD-L1, PD-L2, and JAK2, which has been associated with decreased survival. MATERIALS AND METHODS:Eleven TNBC cell lines were evaluated using array comparative genomic hybridization. A copy number gain was defined as an array comparative genomic hybridization log2 ratio of ≥ 1. Cell surface expression of programmed cell death ligand 1 (PD-L1) was detected using flow cytometry and compared with the median fluorescence intensity of isotype control immunoglobulin. To selectively inhibit JAK2, lentiviral vectors encoding 2 different short hairpin RNA (shRNA) were generated. JAK2, STAT1, STAT3, phosphorylated (p) STAT1, and pSTAT3 expression were measured by immunoblot. Statistical significance was defined as P < .05. RESULTS:The cell line HCC70 had 9p24.1 copy number amplification that was associated with both increased JAK2 and pSTAT3; however, knockdown of JAK2 inhibited cell growth independently of 9p24.1 copy number status. In TNBC cell lines with 9p24.1 gain or amplification, PD-L1 expression rapidly and strikingly increased 5- to 38-fold with interferon-γ (P < .05), and inducible PD-L1 expression was completely blocked by JAK2 knockdown and the JAK1/2 inhibitor ruxolitinib. In tumor tissue, expression of interferon-γ-related genes correlated with 9p24.1 copy number status. CONCLUSION:These data suggest that the JAK2/STAT1 pathway in TNBC might regulate the dynamic expression of PD-L1 that is induced in the setting of an inflammatory response. Inhibition of JAK2 might provide a synergistic therapy when combined with other immunotherapies in the subset of TNBC with 9p24.1 amplification.

journal_name

Clin Breast Cancer

journal_title

Clinical breast cancer

authors

Chen M,Pockaj B,Andreozzi M,Barrett MT,Krishna S,Eaton S,Niu R,Anderson KS

doi

10.1016/j.clbc.2018.05.006

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

e1205-e1215

issue

eissn

1526-8209

issn

1938-0666

pii

S1526-8209(17)30780-2

journal_volume

pub_type

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JAK2 and PD-L1 Amplification Enhance the Dynamic Expression of PD-L1 in Triple-negative Breast Cancer.