PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells

Zheng, Fang; Dang, Jianzhong; Zha, Hui; Zhang, Bingyu; Lin, Ming Tseh; Cheng, Fanjun

doi:10.1155/2017/1293201

Cited by 13 publications

(11 citation statements)

References 36 publications

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“…By increasing expression of apoptosis-related genes, HIF1α usually exhibits a carcinogenic effect in tumor growth, such as in human salivary adenoid cystic carcinoma 22. The antiapoptotic effect of PD-L1, as well as its indicative function of poor prognosis, has been confirmed in tumors,12,23,24 offering a novel insight into developing effective targeted therapies. In the present study, we, for the first time, identified PD-L1 as a downstream target of HIF1α in repressing apoptosis of FTC in hypoxia.…”

Section: Discussionmentioning

confidence: 99%

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<p>HIF1α/PD-L1 axis mediates hypoxia-induced cell apoptosis and tumor progression in follicular thyroid carcinoma</p>

Zhou

Cha²,

Chen

et al. 2019

OTT

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Background Hypoxia-inducible factor 1α (HIF-1α) and programmed cell death-1 protein ligand 1 (PD-L1) are implicated in the metastasis and progression processes of multiple cancers. Hypoxia selectively elevates PD-L1 expression via HIF1α activation in several solid tumors; however, the regulatory effect of HIF1α on PD-L1 in the pathogenesis of follicular thyroid cancer (FTC) remains unclear. This study aims to investigate the regulatory effect of HIF1α on PD-L1 and their potential roles in FTC pathogenesis. Methods Spearman correlation analysis was performed to clarify the relationships between HIF1α and PD-L1 expressions and the clinicopathologic characteristics. The expressions of HIF1α and PD-L1 at mRNA and protein levels were analyzed by qRT-PCR and Western blot. Hypoxia induction and cell transfection were conducted in FTC cells. TUNEL and Annexin V staining were used to detect the cell apoptosis. FTC xenograft tumor models were generated to evaluate the roles of HIF1α and PD-L1 in vivo. Results Here, we found that the expressions of HIF1α and PD-L1 were significantly increased in FTC tissues and were correlated with the FTC clinicopathologic features, such as the tumor size, T stage, TNM staging, and metastasis. In FTC cells, hypoxia-induced increased HIF1α and PD-L1 expression. Knockdown of HIF1α inhibits hypoxia-induced PD-L1 expression and cells apoptosis. Moreover, inhibition of HIF1α or PD-L1 significantly delays tumor growth and metastasis in vivo. Conclusion Hypoxia could promote FTC progression by upregulating HIF1α and PD-L1, which could serve as the molecular targets for FTC treatment.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, PD-L1 overexpression acted as a useful prognostic marker for aggressive FTC and correlated with a great risk of FTC recurrence 10,11. In melanoma cell lines, blocking PD-L1 impairs tumor sphere formation and promotes apoptosis of sphere cells 12. However, the influence of PD-L1 on FTC cell apoptosis has not been clarified yet.…”

Section: Introductionmentioning

confidence: 99%

<p>HIF1α/PD-L1 axis mediates hypoxia-induced cell apoptosis and tumor progression in follicular thyroid carcinoma</p>

Zhou

Cha²,

Chen

et al. 2019

OTT

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“…Recently, several teams reported that independent of immune function, PD-L1 regulated cell growth, proliferation, apoptosis, autophagy, migration and invasion in various cancers including ovarian cancer, melanoma, and pancreatic cancer via modulating PI3K/Akt/mTOR signaling pathway (Clark et al, 2016; Zhao et al, 2017). Additionally, PD-L1 promotes self-renewal and tumorigenicity of malignant melanoma initiating cells (Zheng et al, 2017), as well as embryonic stem cell transcriptional factors octamer-binding transcription factor 4 (OCT4) and Nanog expression dependent on PI3K/Akt activation and B lymphoma Mo-MLV insertion region 1 homolog (BMI1) expression in PI3K/Akt independent manner in breast cancer stem cells (Almozyan et al, 2017). Both evidence suggest the tumor-intrinsic role of PD-L1 in modulating signal transduction and the PD-L1's oncogenic/ tumorigenic role in certain cancers.…”

Section: The Oncogenic Roles Of Endogenous Pd-l1 As a Signaling Proteinmentioning

confidence: 99%

The Prognostic and Therapeutic Value of PD-L1 in Glioma

et al. 2019

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Glioma is the most common type of primary brain tumors. After standard treatment regimen (surgical section, radiotherapy and chemotherapy), the average survival time remains merely around 14 months for glioblastoma (grade IV glioma). Recent immune therapy targeting to the immune inhibitory checkpoint axis, i.e., programmed cell death protein 1 (PD-1) and its ligand PD-L1 (i.e., CD274 or B7-H1), has achieved breakthrough in many cancers but still not in glioma. PD-L1 is considered a major prognostic biomarker for immune therapy in many cancers, with anti-PD-1 or anti-PD-L1 antibodies being used. However, the expression and subcellular distribution of PD-L1 in glioma cells exhibits great variance in different studies, severely impairing PD-L1's value as therapeutic and prognostic biomarker in glioma. The role of PD-L1 in modulating immune therapy is complicated. In addition, endogenous PD-L1 plays tumorigenic roles in glioma development. In this review, we summarize PD-L1 mRNA expression and protein levels detected by using different methods and antibodies in human glioma tissues in all literatures, and we evaluate the prognostic value of PD-L1 in glioma. We also summarize the relationships between PD-L1 and immune cell infiltration in glioma. The mechanisms regulating PD-L1 expression and the oncogenic roles of endogenous PD-L1 are discussed. Further, the therapeutic results of using anti-PD-1/PD-L1 antibodies or PD-L1 knockdown are summarized and evaluated. In summary, current results support that PD-L1 is not only a prognostic biomarker of immune therapy, but also a potential therapeutic target for glioma.

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“…Conversely, knockdown of PD-L1 in MOST-1 cells downregulated expression of anti-apoptotic genes (BCL2 and MCL1) [ 33 ] and silencing of PD-L1 in colorectal cancer cell line and gastric cancer cell lines was associated with an increased apoptotic index [ 50 , 51 ]. In addition, PD-L1 was shown to inhibit the apoptosis of malignant melanoma initiating cells and could contribute to maintaining the stem cell-like properties of these cells [ 56 ]. PD-L1 has also been shown to sustain stem cell-like features in breast cancer cells [ 57 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, increased motility and invasiveness was shown in melanoma cell lines expressing PD-L1 [ 58 ]. PD-L1 was also shown to induce tumor formation in malignant melanoma initiating cells [ 56 ].…”

Section: Introductionmentioning

confidence: 99%

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway

2018

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Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.

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PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells

Cited by 13 publications

References 36 publications

<p>HIF1α/PD-L1 axis mediates hypoxia-induced cell apoptosis and tumor progression in follicular thyroid carcinoma</p>

<p>HIF1α/PD-L1 axis mediates hypoxia-induced cell apoptosis and tumor progression in follicular thyroid carcinoma</p>

The Prognostic and Therapeutic Value of PD-L1 in Glioma

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway

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