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 1

Expression of PD-L1 promotes the EMT and aggressive behaviors in MDA-MB-231 cells.

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Expression of PD-L1 promotes the EMT and aggressive behaviors in MDA-MB-...
(A) Loss of PD-L1 induced epithelial characteristics in TNBC cells. Left panels, cell lysates from the parental or 2 clones of PD-L1–null (KO-1 and KO-2) MDA-MB-231 cells. Right panels, MDA-MB-231 cells transiently transfected with nonspecific control siRNA (siNC) or 2 distinct PD-L1 specific (siPD-L1) siRNAs (si-1 and si-2) for 48 hours. (B) Reexpression of PD-L1 in PD-L1–deficient MDA-MB-231 cells restored the expression of E-cadherin and Snail to levels comparable to the parental cells. Cells were transfected with PD-L1 for 24 hours followed by siPD-L1 (si-1) for another 48 hours. (C) PD-L1 deficiency decreased cell proliferation. Cell proliferation of the parental or PD-L1–deficient cells was determined at 48 hours or 72 hours. (D) Loss of PD-L1 inhibited the anchorage-independent growth. Tumorigenesis potential of control or PD-L1–deficient MDA-MB-231 cells was determined using soft agar colony formation assay. Colony numbers were counted using GelCount. (E) Cells lacking PD-L1 were less migratory. The in vitro cell migration assay was performed using Boyden chamber with 20,000 cells/chamber. Directional cell migration was induced by a 4-hour treatment of 10% FBS in cells serum-starved overnight. (C–E) Results (n = 3 independent experiments) were statistically analyzed and plotted as mean ± SEM using unpaired 2-tailed Student’s t test with the P value adjusted by Bonferroni’s method. *, P < 0.05; **, P < 0.01; ***, P < 0.001.