PD-L1 Expression in Human Breast Cancer Stem Cells Is Epigenetically Regulated through Posttranslational Histone Modifications

Darvin, Pramod; Nair, Varun Sasidharan; Elkord, Eyad

doi:10.1155/2019/3958908

Cited by 58 publications

(45 citation statements)

References 39 publications

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“…In the present study, higher expression of PD-L1 was observed in the CSC population of the CSC culture compared with the CSC population of the WP culture. These results were supported by previous studies, in which PD-L1 expression was positively associated with the expression of stemness markers (20,21), and supported the notion that BCA55-121-CSC cultures possessed CSC properties. In the present study, CSC RNA could be presented as tumor antigens by DCs and activated T cells in the whole T cell population and enriched CD8 + T cells, to stimulate an enhanced ability to kill cancer cells superior to that obtained using RNA from the total BCA55-121 cell population.…”

Section: Discussionsupporting

confidence: 87%

“…The present study revealed that CSCs were more resistant compared with the whole cancer cell population to effector T cells. This may be explained by the finding that the CSC population in CSC cultures expressed high levels of PD-L1 (20), which may induce apoptosis of effector T cells (31). These in vitro findings need to be investigated in an ex vivo system and in clinical trials for the development of DC-based activation of T cells against breast CSCs.…”

Section: Discussionmentioning

confidence: 99%

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Breast cancer stem cell RNA‑pulsed dendritic cells enhance tumor cell killing by effector T�cells�

et al. 2020

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Cancer stem cells (CSCs) underpin the resistance of breast cancer (BC) cells to therapy. Dendritic cell (DC)-based treatment is efficacious and safe, but the efficiency of this technique for targeting CSCs in BC treatment requires further investigation. The present study aimed to investigate the ability of DCs pulsed with breast CSC antigens to activate effector lymphocytes for killing BC cells. CD44 + /CD24-CSCs were isolated from BCA55-121, an in-house patient-derived BC cell line, and acquisition of stemness properties was confirmed by upregulated expression of OCT4A and a superior proliferative capacity in colony formation assays compared with whole population of BCA55-121 (BCA55-121-WP). DCs were differentiated from monocytes from peripheral blood of healthy donors and pulsed with CSC total RNA. Maturation of the CSC RNA-pulsed DCs was confirmed by increased expression of CD11c, CD40, CD83, CD86 and HLA-DR, as well as reduced CD14 expression compared with monocytes. Total lymphocytes co-cultured with CSC RNA-pulsed DCs were analyzed by flow cytometry for markers including CD3, CD4, CD8, CD16 and CD56. The results revealed that the co-cultures contained mostly cytotoxic CD8 + T lymphocytes followed by CD4 + T lymphocytes and smaller populations of natural killer (NK) and NKT cells. ELISA was used to measure IFN-γ production, and it was revealed that activated CD4 + and CD8 + lymphocytes produced more IFN-γ compared with naïve T cells, suggesting that CD8 + T cells were effector T cells. CSC RNA was a more efficient antigen source compared with RNA from mixed BC cells for activating tumor antigen-specific killing by T cells. These CSC-specific effector T cells significantly induced BC cell apoptosis at a 20:1 effector T cell:tumor cell ratio. Of note, the breast CSCs cultures demonstrated resistance to effector T cell killing, which was in part due to increased expression of programmed death ligand 1 in the CSC population. The present study highlights the potential use of CSC RNA for priming DCs in modulating an anticancer immune response against BC.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Breast cancer stem cell RNA‑pulsed dendritic cells enhance tumor cell killing by effector T�cells�

et al. 2020

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“…Histone H3 acetylation of the PD-L1 promoter is increased and mediated by the c-Jun/HDAC3 axis in drugresistant A549/CDDP, MCF7/ADR and HepG2/ADR cells Epigenetic modifications, such as DNA methylation and histone acetylation, are frequently involved in regulating PD-L1 expression in cancer cells [23][24][25]. First, a total of 18 CpG islands in the PD-L1 promoter region were sequenced, and the DNA methylation of the PD-L1 promoter region was barely changed in the drug-resistant cancer cells in our study (Additional file 1: Figure S3).…”

Section: Resultsmentioning

confidence: 99%

“…Accumulating evidence demonstrates that epigenetic modifications such as DNA methylation and histone acetylation are frequently involved in PD-L1 expression in cancer cells [23,25]. Methylation of CpG islands over the PD-L1 promoter region negatively regulates PD-L1 transcription [39].…”

Section: Discussionmentioning

confidence: 99%

Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells

Wang

et al. 2020

J Exp Clin Cancer Res

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Background: Drug resistance is a major obstacle to treating cancers because it desensitizes cancer cells to chemotherapy. Recently, attention has been focused on changes in the tumor immune landscape after the acquisition of drug resistance. Programmed death-ligand-1 (PD-L1) is an immune suppressor that inhibits T cellbased immunity. Evidence has shown that acquired chemoresistance is associated with increased PD-L1 expression in cancer cells. However, the underlying mechanism is still largely unknown. Methods: PD-L1 expression in three drug-resistant A549/CDDP, MCF7/ADR and HepG2/ADR cell lines was detected by qRT-PCR, western blotting and flow cytometry, and a T cell proliferation assay was performed to test its functional significance. Then, the potential roles of JNK/c-Jun, histone H3 acetylation, histone deacetylase 3 (HDAC3) and the E3 ligase COP1 in the PD-L1 increase were explored through ChIP assays and gain-and loss-of-function gene studies. Furthermore, murine xenograft tumor models were used to verify the role of JNK/c-Jun and HDAC3 in PD-L1 expression in A549/CDDP cells in vivo. Finally, the correlations of PD-L1, c-Jun and HDAC3 expression in clinical cisplatin-sensitive and cisplatin-resistant non-small cell lung cancer (NSCLC) tissues were analyzed by immunohistochemistry and Pearson's correlation coefficient. Results: PD-L1 expression was significantly increased in A549/CDDP, MCF7/ADR and HepG2/ADR cells and was attributed mainly to enhanced JNK/c-Jun signaling activation. Mechanistically, decreased COP1 increased c-Jun accumulation, which subsequently inhibited HDAC3 expression and thereby enhanced histone H3 acetylation of the PD-L1 promoter. Furthermore, PD-L1 expression could be inhibited by JNK/c-Jun inhibition or HDAC3 overexpression in vivo, which could largely reverse inhibited CD3 + T cell proliferation in vitro. PD-L1 expression was significantly increased in the cisplatin-resistant clinical NSCLC samples and positively correlated with c-Jun expression but negatively correlated with HDAC3 expression.

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“…Mathematical model-based analysis can also be used to comment on the possibility of tumor initiation within a clinically observable time with respect to the presence of BCSCs [28]. Here, we note that the high levels of PD-1/PD-L1 expression reported on CSCs are believed to aid immune evasion [180,181]. The expression of PD-L1 in BCSC is linked to enhancing the presence of transcription factors such as OCT-4A and Nanog [180].…”

Section: Mathematical Models Used For Breast Cancer Managementmentioning

confidence: 95%

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Padmanabhan

Kheraldine

Meskin

et al. 2020

Cancers

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Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2+) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2+ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2+ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2+ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2+ breast cancer and immune checkpoint inhibitors.

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PD-L1 Expression in Human Breast Cancer Stem Cells Is Epigenetically Regulated through Posttranslational Histone Modifications

Cited by 58 publications

References 39 publications

Breast cancer stem cell RNA‑pulsed dendritic cells enhance tumor cell killing by effector T�cells�

Breast cancer stem cell RNA‑pulsed dendritic cells enhance tumor cell killing by effector T�cells�

Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

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