Downregulation of HLA Class I Molecules in Primary Oral Squamous Cell Carcinomas and Cell Lines

2009 ◽  
Vol 40 (4) ◽  
pp. 256-263 ◽  
Author(s):  
Qiusha Tang ◽  
Jianqiong Zhang ◽  
Bing Qi ◽  
Chuanlai Shen ◽  
Wei Xie
Keyword(s):  
Cell Lines ◽  
Squamous Cell ◽  
Hla Class I ◽  
Squamous Cell Carcinomas ◽  
Class I ◽  
Oral Squamous Cell Carcinomas ◽  
Hla Class I Molecules

Cell lines of human oral squamous-cell carcinomas retaining their differentiated phenotype

1990 ◽  
Vol 45 (5) ◽  
pp. 945-951 ◽  
Author(s):  
R. P. M. A. Crooijmans ◽  
J. H. M. Schwachöfer ◽  
J. Hoogenhout ◽  
G. Merkx ◽  
L. G. Poels ◽  
...  
Keyword(s):  
Cell Lines ◽  
Squamous Cell ◽  
Squamous Cell Carcinomas ◽  
Oral Squamous Cell Carcinomas

844 Immunomodulatory activity of epigenetic drugs combinations in mesothelioma: laying the ground for new immunotherapeutic strategies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A896-A896
Author(s):  
Sara Cannito ◽  
Health Biology ◽  
Ornella Cutaia ◽  
Carolina Fazio ◽  
Maria Fortunata Lofiego ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Hla Class I ◽  
Class I ◽  
Immunomodulatory Activity ◽  
Epigenetic Drugs ◽  
Hla Class I Antigens ◽  
Hla Class I Molecules ◽  
Mesothelioma Cell Line ◽  
Mesothelioma Cell

BackgroundGrowing evidence are demonstrating the therapeutic efficacy of immune checkpoint inhibitors (ICI) in mesothelioma; however, a limited percentage of patients benefits from this therapeutic approach. Epigenetic modifications play a relevant role in negatively regulating the cross-talk between neoplastic and immune cells, and in contributing to the highly immunosuppressive mesothelioma microenvironment. A better understanding of mesothelioma epigenetic landscape could open the path to novel and potentially more effective approaches combining ICI and epigenetic drugs. We investigated the immunomodulatory potential of epigenetic agents by comparing the activity of DNA hypomethylating agents (DHA) with histone deacetylases inhibitors (HDACi) and EZH2 inhibitors (EZH2i), alone or combined with DHA, in mesothelioma cells.MethodsFour mesothelioma cell lines were treated with the DHA guadecitabine 1μM, or with the HDACi, Valproic Acid (VPA) 1mM, or the EZH2i, EPZ-6438 1μM, alone or combined with guadecitabine. We investigated the expression of HLA class I molecules by flow-cytometry and of PD-L1, cancer testis antigens (CTA: NY-ESO, MAGE-A1), Natural Killer Group 2 member D Ligands (NKG2DLs: MIC-A, MIC-B, ULBP2) and EMT-regulating cadherins (CDH1, CDH2) by quantitative Real-Time PCR. Fold change (FC) expression for each treatment vs untreated cells was reported as mean values (FCm) among investigated cell lines. A positive modulation of the expression was considered if FCm>1.5.ResultsGuadecitabine upregulated the expression of HLA class I antigens (FCm=1.75), PD-L1 (FCm=2.38), NKG2DLs (MIC-A FCm=1.96, MIC-B FCm=2.57, and ULBP2 FCm=3.56), and upregulated/induced CTA expression. Similarly, VPA upregulated HLA class I antigens (FCm=1.67), PD-L1 (FCm=3.17), NKG2DLs (MIC-A FCm=1.78, MIC-B FCm=3.04, and ULBP2 FCm=3.75) expression; however, CTA expression was modulated only in 1 mesothelioma cell line. Conversely, EPZ-6438 up-regulated only NY-ESO-1 and MIC-B expression in 1 mesothelioma cell line.The addition of both VPA and EPZ-6483 to guadecitabine strengthened its immunomodulatory activity. Specifically, guadecitabine plus VPA or EPZ-6438 upregulated the expression of HLA class I antigens FCm=2.55 or 2.69, PD-L1 FCm=8.04 or 2.65, MIC-A FCm=3.81 or 2.26, MIC-B FCm=8.00 or 3.03, ULBP2 FCm=6.24 or 4.53, respectively. Higher levels of CTA upregulation/induction were observed with combination treatments vs guadecitabine alone.Cadherins modulation was mesothelioma histotype-related: CDH1 expression was induced in the 2 constitutively-negative sarcomatoid mesothelioma cells by guadecitabine alone or combined with VPA or EPZ-6438; CDH2 expression was upregulated by VPA alone (FCm=1.53) or plus guadecitabine (FCm=2.54).ConclusionsCombination of DHA-based immunotherapies with other classes of epigenetic drugs could be an effective strategy to be pursued in the mesothelioma clinic.

Multi-Drug Resistant Leukemic Cells Highly Express HLA Class I Molecules and Single-Chain Fv Diabody Specific to HLA-A Overcomes Drug Resistance in These Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2376-2376
Author(s):  
Ali Jalili ◽  
Shuji Ozaki ◽  
Naoki Kimura ◽  
Masahiro Abe ◽  
Toshio Matsumoto
Keyword(s):  
Tumor Cells ◽  
Cell Lines ◽  
Hla Class I ◽  
Resistant Cell ◽  
Class I ◽  
Single Chain ◽  
Expression Levels ◽  
Hla Class I Molecules ◽  
Single Chain Fv ◽  
Mdr 1

Abstract Many tumor cells become resistant to commonly used cytotoxic drugs due to the overexpression of ATP-binding cassette (ABC) transporters. Specifically, p-glycoprotein (MDR-1) is frequently up-regulated in chemotherapy-resistant tumor cells, which is associated with poor prognosis. On the other hand, human leukocyte antigen (HLA) class I molecules are known to be significantly down-regulated in advanced tumor cells to escape from immune surveillance. However, the relationship between MDR-1 expression and HLA expression is not fully understood. Recently, we have developed a recombinant single-chain Fv diabody specific to HLA-A and demonstrated that this agent mediates cell death in HLA-overexpressing lymphoid tumor cells but not in normal cells (Cancer Res2007; 67:1184). Here, we investigated the expression levels of HLA class I in chemo-resistant leukemic cells and evaluated the therapeutic potential of single-chain Fv diabody specific to HLA-A, C3B3-DB (Chugai Pharmaceutical Co. Ltd., Tokyo, Japan). Chemotherapy-resistant cells were established by subculturing of myeloid leukemia cell line HL60 and Burkitt’s lymphoma cell line BL-TH in increasing doses of vincristine (VCR), and named HL60/VCR and BL-TH/VCR, respectively. MDR-1 is strongly expressed in HL60/VCR and BL-TH/VCR cells both at the mRNA and protein levels, but not in the parental cells. Interestingly, expression levels of HLA class I molecules are 8 times higher in HL60/VCR and BL-TH/VCR cells than in the parental cells, suggesting that MDR-1 modulates cell surface expression of HLA by its transporter function. Next, we examined the cytotoxic activity of C3B3-DB on these chemo-resistant cell lines. C3B3-DB induced apoptosis in HL60/VCR and BL-TH/VCR cells and these chemo-resistant cell lines were more sensitive to C3B3-DB than the parent cells. Combination of C3B3-DB with chemotherapeutic agents such as VCR and daunorubicin (DNR) resulted in enhanced cytotoxicity against HL60/VCR and BL-TH/VCR cells. Importantly, pretreatment of these chemo-resistant cell lines with C3B3-DB reduced expression levels of MDR-1 and increased drug retention in these cells as detected by flow cytometry and confocal microscopy. Furthermore, combination of C3B3-DB with VCR significantly blocked the cell cycle at the G2 phase compared with VCR alone. Similar results were obtained with primary acute myeloid leukemia cells from 2 patients, resulting in up-regulation of both HLA class I and MDR-1 molecules at relapse phase compared at diagnosis. These results suggest that C3B3-DB enhances cytotoxicity of chemotherapeutic agents and provides a novel approach for overcoming drug resistance in hematological malignancies.

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