PD-L1 tumor-intrinsic signaling and its therapeutic implication in triple-negative breast cancer
Chunhua Chen, … , Haidong Dong, Kun Ling
Chunhua Chen, … , Haidong Dong, Kun Ling
Published April 22, 2021
Citation Information: JCI Insight. 2021;6(8):e131458. https://doi.org/10.1172/jci.insight.131458.
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Research Article Oncology Therapeutics

PD-L1 tumor-intrinsic signaling and its therapeutic implication in triple-negative breast cancer

Abstract

Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutics development, partly because of the incomplete mechanistic understanding. Here we demonstrate a potentially novel mechanism by which PD-L1 promotes the epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells by suppressing the destruction of the EMT transcription factor Snail. PD-L1 directly binds to and inhibits the tyrosine phosphatase PTP1B, thus preserving p38-MAPK activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β). Via this mechanism, PD-L1 prevents the GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail and consequently promotes the EMT and metastatic potential of TNBC. Significantly, PD-L1 antibodies that confine the tumor-intrinsic PD-L1/Snail pathway restricted TNBC progression in immunodeficient mice. More importantly, targeting both tumor-intrinsic and tumor-extrinsic functions of PD-L1 showed strong synergistic tumor suppression effect in an immunocompetent TNBC mouse model. Our findings support that PD-L1 intrinsically facilitates TNBC progression by promoting the EMT, and this potentially novel PD-L1 signaling pathway could be targeted for better clinical management of PD-L1–overexpressing TNBCs.

Authors

Chunhua Chen, Shiheng Li, Junli Xue, Manlong Qi, Xin Liu, Yan Huang, Jinghua Hu, Haidong Dong, Kun Ling

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Figure 7

PD-L1 antibodies diminish PD-L1 tumor-intrinsic signaling and inhibit TNBC progression independent of antitumor immunity.

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PD-L1 antibodies diminish PD-L1 tumor-intrinsic signaling and inhibit TN...
(A) PD-L1 antibodies suppressed PD-L1 expression and signaling. MDA-MB-231 cells were treated with control IgG, H1A, or B11 for 48 hours before being subjected to immunoblotting. Relative p38 activity was calculated as the ratio of phosphorylated p38 and total p38, then normalized against the control group (IgG). Data were plotted as mean ± SEM and statistically analyzed using unpaired 2-tailed Student’s t test with the P value adjusted by Bonferroni’s method (n = 3 independent experiments). *, P < 0.05; **, P < 0.01. (B–F) NOD/SCID mice receiving 2 × 106 MDA-MB-231 cells in mammary fat pad were separated into 3 treatment groups (IgG, H1A, or B11). Starting from day 4 after inoculation, 200 μg antibodies were administrated intraperitoneally every 3 days until termination. (B and C) Tumor was measured weekly (B) and weighed at the endpoint (C). (D) Survival (Kaplan-Meier) curve was summarized in each treatment group. (E) Micrometastatic lesions in lung tissues from each treatment group were visualized by H&E staining and quantified. Power of eyepiece: 10×; power of objective: 10×. (F) Treatment of PD-L1 antibodies inhibited PD-L1 signaling. The number of phosphorylated p38-positive or Snail-positive cells in tumor tissues was determined by immunohistochemistry staining in tandem tissue slides prepared from tumors treated with control or PD-L1 antibodies. Power of eyepiece: 10×; power of objective: 20×. (E and F) Values from more than 10 fields in slide from each mouse were quantified and averaged. (B–F) Data for each group were plotted as mean ± SEM, and comparisons with the mouse IgG group were statistically analyzed using 1-way ANOVA analysis with Dunnett’s test (n = 11–13 mice/group). *, P < 0.05; **, P < 0.01; ***, P < 0.001.