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

Meixuan Chen, Barbara Pockaj, Mariacarla Andreozzi, Michael T. Barrett, Sri Krishna, Seron Eaton, Ruifang Niu, Karen Anderson

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The present study evaluated the interaction between the JAK2 and programmed cell death ligand 1 (PD-L1) pathways in triple-negative breast cancer (TNBC). A subset of TNBC tumors had a 9p24.1 amplification encoding JAK2 and PD-L1. We observed a synergy between the JAK2/interferon-γ pathway and 9p24.1 amplification, leading to increased PD-L1 expression. 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.

Original languageEnglish (US)
Pages (from-to)e1205-e1215
JournalClinical Breast Cancer
Volume18
Issue number5
DOIs
StatePublished - Oct 2018

Keywords

  • Biomarker
  • Checkpoint blockade
  • Immunotherapy
  • Programmed cell death ligand 1
  • TNBC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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