PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines

Lotfinejad, Parisa; Kazemi, Tohid; Safaei, Sahar; Amini, Mohammad; Asl, Elmira Roshani; Baghbani, Elham; Shotorbani, Siamak Sandoghchian; Niaragh, Farhad Jadidi; Derakhshani, Afshin; Silvestris, Nicola; Baradaran, Behzad

doi:10.1016/j.biopha.2021.111436

Cited by 36 publications

(31 citation statements)

References 51 publications

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“…Previous study has shown that the knockdown of PD-L1 reduces tumor growth and metastasis [7,9]. We therefore employed two tumor models for in vivo research, including lung metastasis model and orthotropic tumor model.…”

Section: Hdac2 Knockout Impaired Tumor Growth and Pd-l1 Production In Vivomentioning

confidence: 99%

“…A study has shown that the PD-L1 expression is significantly higher in TNBC and HER2+ subtypes, which positively correlates with the 3 rd histology level and lymph node metastasis, indicating that PD-L1 is a biomarker of poor prognosis [8]. Experiments in vitro showed that the inhibition of proliferation and migration, high rate of apoptosis were observed after PD-L1 knockdown in TNBC cells [9]. To date, the clinical trials of immunotherapies based on the PD-1/PD-L1 antagonists have shown a notable and durable response in TNBC patients [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression

Xiong

Lin

et al. 2021

Cell Death Dis

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The PD-L1 overexpression is an important event of immune escape and metastasis in triple-negative breast cancer (TNBC), but the molecular mechanism remains to be determined. Interferon gamma (IFNγ) represents a major driving force behind PD-L1 expression in tumor microenvironment, and histone deacetylase 2 (HDAC2) is required for IFN signaling. Here, we investigated the regulation of HDAC2 on the IFNγ-induced PD-L1 expression in TNBC cells. We found the HDAC2 and PD-L1 expression in TNBC was significantly higher than that in non-TNBC, and HDAC2 was positively correlated with PD-L1 expression. HDAC2 promoted PD-L1 induction by upregulating the phosphorylation of JAK1, JAK2, and STAT1, as well as the translocation of STAT1 to the nucleus and the recruitment of STAT1 to the PD-L1 promoter. Meanwhile, HDAC2 was recruited to the PD-L1 promoter by STAT1, and HDAC2 knockout compromised IFNγ-induced upregulation of H3K27, H3K9 acetylation, and the BRD4 recruitment in PD-L1 promoter. In addition, significant inhibition of proliferation, colony formation, migration, and cell cycle of TNBC cells were observed following knockout of HDAC2 in vitro. Furthermore, HDAC2 knockout reduced IFNγ-induced PD-L1 expression, lymphocyte infiltration, and retarded tumor growth and metastasis in the breast cancer mouse models. This study may provide evidence that HDAC2 promotes IFNγ-induced PD-L1 expression, suggesting a way for enhanced antitumor immunity when targeting the HDAC2 in TNBC.

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Section: Hdac2 Knockout Impaired Tumor Growth and Pd-l1 Production In Vivomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression

Xiong

Lin

et al. 2021

Cell Death Dis

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“…Indeed, Lotfinejad et al. have indicated that PD-L1 silencing remarkably downregulates the expression of CD44 in TNBC cells ( 37 ). Zhang et al.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Lotfinejad et al. have shown that inhibiting tumoral PD-L1 can substantially decrease CD44 expression in TNBC cells ( 37 ). Besides, inhibiting CD44 has been associated with decreased expression of PD-L1 in TNBC cells ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

“…This axis can be established between tumoral cells and effector immune cells and shield the tumoral cells from anti-tumoral immune responses (40). Recently, Lotfinejad et al have shown that inhibiting tumoral PD-L1 can substantially decrease CD44 expression in TNBC cells (37). Besides, inhibiting CD44 has been associated with decreased expression of PD-L1 in TNBC cells (15).…”

Section: Lessons From the Past And The Road Aheadmentioning

confidence: 99%

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A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

et al. 2021

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As a unique population of tumor bulk, cancer stem cells have been implicated in tumor relapse and chemoresistance in triple-negative breast cancer (TNBC). Therefore, understanding the phenotype of cancer stem cells can pave the way for introducing novel molecular targeted therapies for treating TNBC patients. Preclinical studies have identified CD44+CD24-/low as a cancer stem cell phenotype; however, clinical studies have reported seemingly controversial results regarding the prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients. To critically review the clinicopathological significance and prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients, the Scopus, Embase, PubMed, and Web of Science databases were systematically searched to obtain the relevant records published before 20 October 2020. Based on nine included studies, CD44 and CD44+CD24-/low phenotype are associated with inferior prognosis in TNBC patients. Moreover, these cancer stem cell markers have been associated with advanced tumor stage, tumor size, higher tumor grade, tumor metastasis, and lymphatic involvement in TNBC patients. Our evidence has also indicated that, unlike the treatment-naïve TNBC patients, the tumoral cells of chemoradiotherapy-treated TNBC patients can upregulate the CD44+CD24-/low phenotype and establish an inverse association with androgen receptor (AR), leading to the inferior prognosis of affected patients. In summary, CD44 and CD44+CD24-/low phenotype can be utilized to determine TNBC patients’ prognosis in the pathology department as a routine practice, and targeting these phenotypes can substantially improve the prognosis of TNBC patients.

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Silencing of COL3A1 represses proliferation, migration, invasion, and immune escape of triple negative breast cancer cells via down‐regulating PD‐L1 expression

Yang

et al. 2022

Cell Biology International

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This study is designed to illuminate the specific role and underlying mechanism of collagen type III alpha 1 chain (COL3A1) in triple negative breast cancer (TNBC).Quantitative real-time polymerase chain reaction was applied to examine mRNA expression of COL3A1. Western blot analysis was employed to determine protein levels of COL3A1, programmed death ligand 1 (PD-L1), Bcl-2, and cleaved caspase-3. Immunohistochemistry staining was utilized for assessing protein expression of Ki67 and COL3A1 in tissues. The proliferous capacity of cells was assessed through CCK-8 assay and 5-Ethynyl-2′-deoxyuridine assay. Cell apoptosis and the percentage of CD8 + T cells were measured using flow cytometry. Migration and invasion of TNBC cells were examined via transwell assay. Lactate dehydrogenase (LDH) release was measured via a LDH assay kit. For establishing a xenograft tumor model, MDA-MB-231 cells were injected into the flank of mice through subcutaneous injection. COL3A1 expression was raised in TNBC tissues and cells, and it was inversely associated with overall survival data of TNBC patients. COL3A1 downregulation repressed proliferation, invasion, migration, and immune escape of TNBC cells along with tumor growth of xenograft mice. In TNBC cells and tumor tissues of mice, protein expression of PD-L1 was reduced by COL3A1 knockdown. COL3A1 knockdown-mediated inhibitory effects on cell proliferation, migration, invasion, and immune escape were reversed by PD-L1 upregulation in vitro. Silencing of COL3A1 exerted an antitumor role in TNBC, implying its potential as a therapeutic target for TNBC.

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PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines

Cited by 36 publications

References 51 publications

Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression

Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression

A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

Silencing of COL3A1 represses proliferation, migration, invasion, and immune escape of triple negative breast cancer cells via down‐regulating PD‐L1 expression

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