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. 2018 Oct;18(5):e1205-e1215.
doi: 10.1016/j.clbc.2018.05.006. Epub 2018 May 26.

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

Meixuan Chen  1 , Barbara Pockaj  2 , Mariacarla Andreozzi  3 , Michael T Barrett  3 , Sri Krishna  4 , Seron Eaton  5 , Ruifang Niu  6 , Karen S Anderson  7
Affiliations
Free article

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

Meixuan Chen et al. Clin Breast Cancer. 2018 Oct.
Free article

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] Clin Breast Cancer. 2019 Feb;19(1):87-88. doi: 10.1016/j.clbc.2018.12.016. Clin Breast Cancer. 2019. PMID: 30691704 No abstract available.

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.

Keywords: Biomarker; Checkpoint blockade; Immunotherapy; Programmed cell death ligand 1; TNBC.

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