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

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

doi:10.1172/jci.insight.131458

Cited by 51 publications

(66 citation statements)

References 63 publications

(81 reference statements)

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“…Our findings in this study add much to published reports on advantages given to tumor cells by expressing PD-L1. The approach generally taken so far was to knock-out/knockdown PD-L1 expression in breast cancer cells or to inhibit it by antibodies; such studies have shown that down-regulation of PD-L1 has led to inhibition of tumor cell proliferation and migration, to reduction in EMT-related properties of the cells and to the expression of CSC-related properties [ 31 , 32 , 33 , 34 ]. Under conditions of PD-L1 knock-down, the ability of TNBC cells to form primary tumors was not modified, but the metastatic process was inhibited [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…To date, only a limited number of publications have addressed the possibility that PD-L1 would act in an autonomous manner in breast cancer cells; these reports have used PD-L1 down-regulation or inhibition and demonstrated intrinsic PD-L1 activities in a few aspects of malignancy [ 31 , 32 , 33 , 34 ]. In our study, we extended these observations by taking the approach of up-regulating PD-L1 expression, in multiple breast tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Erlichman

Baram

Meshel

et al. 2022

Cancers

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Therapies targeting the PD-L1/PD-1 axis have recently been introduced to triple-negative breast cancer (TNBC) with limited efficacy, suggesting that this axis promotes tumor progression through mechanisms other than immune suppression. Here, we over-expressed WT-PD-L1 in human TNBC cells (express endogenous PD-L1) and in luminal-A breast cancer cells (no endogenous PD-L1 expression) and demonstrated that cell-autonomous PD-L1 activities lead to increased tumor cell growth, invasion and release of pro-metastatic factors (CXCL8, sICAM-1, GM-CSF). These activities were promoted by PD-1 and were inhibited by mutating S283 in PD-L1. Invasion of WT-PD-L1-cells required signaling by chemokine receptors CXCR1/2, CCR2 and CCR5 through autocrine circuits involving CXCL8, CCL2 and CCL5. Studies with T cell-deficient mice demonstrated that cell-autonomous WT-PD-L1 activities in TNBC cells increased tumor growth and metastasis compared to knock-out (KO)-PD-L1-cells, whereas S283A-PD-L1-expressing cells had minimal ability to form tumors and did not metastasize. Overall, our findings reveal autonomous and PD-1-induced tumor-promoting activities of PD-L1 that depend on S283 and on chemokine circuits. These results suggest that TNBC patients whose tumors express PD-L1 could benefit from therapies that prevent immune suppression by targeting PD-1/CTLA-4, alongside with antibodies to PD-L1, which would allow maximal impact by mainly targeting the cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Erlichman

Baram

Meshel

et al. 2022

Cancers

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“…Two studies showed that PD-L1 can inhibit GSK3β activity via binding to tyrosine phosphatase PTP1B or integrin β4 to activate p38-MAPK or Akt activity, respectively. Through this mechanism, PD-L1 can inhibit GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail1, thereby promoting EMT and the metastatic potential of breast cancer and cervical cancer ( 135 , 136 ).…”

Section: Bidirectional Regulation Of Snail1 and Tumor Immune Environment In Tumor Progressionmentioning

confidence: 99%

SNAIL1: Linking Tumor Metastasis to Immune Evasion

et al. 2021

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The transcription factor Snail1, a key inducer of epithelial-mesenchymal transition (EMT), plays a critical role in tumor metastasis. Its stability is strictly controlled by multiple intracellular signal transduction pathways and the ubiquitin-proteasome system (UPS). Increasing evidence indicates that methylation and acetylation of Snail1 also affects tumor metastasis. More importantly, Snail1 is involved in tumor immunosuppression by inducing chemokines and immunosuppressive cells into the tumor microenvironment (TME). In addition, some immune checkpoints potentiate Snail1 expression, such as programmed death ligand 1 (PD-L1) and T cell immunoglobulin 3 (TIM-3). This mini review highlights the pathways and molecules involved in maintenance of Snail1 level and the significance of Snail1 in tumor immune evasion. Due to the crucial role of EMT in tumor metastasis and tumor immunosuppression, comprehensive understanding of Snail1 function may contribute to the development of novel therapeutics for cancer.

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“…A CAGE-derived peptide enhanced the sensitivity of melanoma cells to anti-cancer drugs by disrupting CAGE-GSK3β interaction [ 126 ]. As with CAGE, PD-L1 could bind to the EGFR and inactivate GSK3β [ 124 ]. Thus, combining a miR-200 family miRNA-mimic and a CAGE-derived peptide can overcome resistance to immune check inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…PD-L1 served as a target of miR-200a in non-small cell lung cancer cells [ 123 ]. PD-L1 promoted EMT by preventing glycogen synthase kinase 3β (GSK3β) from degrading SNAIL in triple-negative breast cancer cells [ 124 ] ( Figure 4 C). PD-L1 bound to the EGFR and promoted TNF-related apoptosis-inducing ligand (TRAIL) resistance in gastric cancer cells [ 125 ] ( Figure 4 C).…”

Section: Role Of the Mir-200 Family In Anti-cancer Drug Resistancementioning

confidence: 99%

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

Shim

Jeoung

2022

IJMS

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MicroRNAs (miRNAs) are small non-coding RNAs (18–24 nucleotides) that play significant roles in cell proliferation, development, invasion, cancer development, cancer progression, and anti-cancer drug resistance. miRNAs target multiple genes and play diverse roles. miRNAs can bind to the 3′UTR of target genes and inhibit translation or promote the degradation of target genes. miR-200 family miRNAs mostly act as tumor suppressors and are commonly decreased in cancer. The miR-200 family has been reported as a valuable diagnostic and prognostic marker. This review discusses the clinical value of the miR-200 family, focusing on the role of the miR-200 family in the development of cancer and anti-cancer drug resistance. This review also provides an overview of the factors that regulate the expression of the miR-200 family, targets of miR-200 family miRNAs, and the mechanism of anti-cancer drug resistance regulated by the miR-200 family.

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

Cited by 51 publications

References 63 publications

Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

SNAIL1: Linking Tumor Metastasis to Immune Evasion

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

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