High frequency of allele-specific down-regulation of HLA class I expression in uveal melanoma cell lines

Hurks, H. M. H.; Metzelaar-Blok, Jessica A. W.; Mulder, Arend; Claas, Frans H.J.; Jager, Martine J.

doi:10.1002/(sici)1097-0215(20000301)85:5<697::aid-ijc16>3.0.co;2-h

Cited by 30 publications

(5 citation statements)

References 27 publications

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“…This made us wonder what exactly regulates HLA expression levels in UM: chromosomal dose effects (gain or loss of chromosome 6), an intrinsic genetic regulation, or external influences. We know that occasionally specific HLA alleles are not expressed [ 21 ]. Therefore we looked in a previous study at the association between HLA expression and LOH (Loss of Heterozygosity) of chromosome 6 [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes

et al. 2016

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IntroductionUveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors should be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors.Methods28 enucleated UM were used to study HLA class I and II expression, and several regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome SNP-array. Fresh tumor samples of eight primary UM and four metastases were compared to their corresponding xenograft in SCID mice, using a PCR microarray and SNP array.ResultsIncreased expression levels of HLA class I and II showed no dosage effect of chromosome 6p, but, as expected, were associated with monosomy of chromosome 3. Increased HLA class I and II protein levels were positively associated with their gene expression and with raised levels of the peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, and NLRC5, revealing a higher transcriptional activity in prognostically-bad tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of infiltrating leukocytes, and to a decreased expression of HLA class I and II genes, and their regulators.ConclusionOur data provides evidence for a proper functioning HLA regulatory system in UM, offering a target for T-cell based therapies.

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Section: Introductionmentioning

confidence: 99%

Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes

et al. 2016

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“…Conversely, additional studies have shown that a differential regulation of the expression of HLA‐A and ‐B loci associates with malignant transformation of melanocytes, leading to a constitutively down‐regulated expression of HLA‐B antigens in melanomas and melanoma cell lines3 and most recently in uveal melanoma cell lines 4. Different mechanisms have been suggested to be responsible for this phenomenon, among these: i) high levels of the c ‐ myc oncogene or of p53 that suppress HLA‐B expression;5 ii) an increased frequency of the binding of transcriptional repressors to the interferon‐stimulated response element (ISRE) located at HLA‐B promoter;6 iii) the presence of regulatory regions, with different nucleotide sequences and binding activities between HLA‐A and ‐B loci, that mediate transcriptional repression of HLA‐B locus 7, 8.…”

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confidence: 99%

Unbalanced expression of HLA-A and -B antigens: A specific feature of cutaneous melanoma and other non-hemopoietic malignancies reverted by IFN-?

et al. 2001

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Conflicting evidences suggested that levels of HLA‐A and ‐B antigens expressed on normal and neoplastic cells of given individuals are genetically predetermined, or, on the other hand, regulated by molecular mechanisms generating the down‐regulated expression of HLA‐B antigens frequently observed on melanoma cells. In our study, we quantitated, both at the protein and mRNA level, the amounts of HLA‐A and ‐B antigens constitutively expressed on 23 primary cultures of metastatic melanomas and on autologous peripheral blood mononuclear cells (PBMC). Flow cytometric analyses identified a significantly (p < 0.01) lower expression of HLA‐B antigens on melanoma cell cultures but not on autologous PBMC. Consistently, lower amounts of HLA‐B antigens mRNA were detected by RNase protection assay exclusively in neoplastic cells. This unbalanced expression of HLA‐A and ‐B antigens was readily reverted by interferon (IFN)‐γ but not by the DNA hypomethylating agent 5‐aza‐2′‐deoxycytidine in 4 melanoma cell cultures investigated. Significantly (p < 0.05) lower levels of HLA‐B antigens were also detected on cells from solid malignancies of different histotypes but not on neoplastic cells from hemopoietic neoplasms; levels of HLA‐B antigens were rapidly up‐regulated by IFN‐γ exclusively on non‐hemopoietic transformed cells. Together, these data strongly argue against a genetic predetermination of the amounts of HLA‐A and ‐B antigens expressed on normal and neoplastic cells of distinct melanoma patients and suggest that constitutively low levels of HLA‐B antigens are a specific feature of non‐hemopoietic transformed cells that is controlled by common regulatory mechanism(s) and that is possibly shared by non‐hemopoietic normal cells. © 2001 Wiley‐Liss, Inc.

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“…However, uveal melanoma cells can maintain some level of HLA expression while at the same time undergoing HLA downregulation for certain HLA loci and alleles. That way it can potentially evade both T cell killing as well as NK cell targeting [107].…”

Section: Role Of Tumor Hla Expressionmentioning

confidence: 99%

Role of Natural Killer Cells in Uveal Melanoma

Javed

Milhem

2020

Cancers

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Uveal melanoma has a high mortality rate following metastasis to the liver. Despite advances in systemic immune therapy, treatment of metastatic uveal melanoma (MUM) has failed to achieve long term durable responses. Barriers to success with immune therapy include the immune regulatory nature of uveal melanoma as well as the immune tolerant environment of the liver. To adequately harness the anti-tumor potential of the immune system, non-T cell-based approaches need to be explored. Natural Killer (NK) cells possess potent ability to target tumor cells via innate and adaptive responses. In this review, we discuss evidence that highlights the role of NK cell surveillance and targeting of uveal melanoma. We also discuss the repertoire of intra-hepatic NK cells. The human liver has a vast and diverse lymphoid population and NK cells comprise 50% of the hepatic lymphocytes. Hepatic NK cells share a common niche with uveal melanoma micro-metastasis within the liver sinusoids. It is, therefore, crucial to understand and investigate the role of intra-hepatic NK cells in the control or progression of MUM.

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High frequency of allele-specific down-regulation of HLA class I expression in uveal melanoma cell lines

Cited by 30 publications

References 27 publications

Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes

Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes

Unbalanced expression of HLA-A and -B antigens: A specific feature of cutaneous melanoma and other non-hemopoietic malignancies reverted by IFN-?

Role of Natural Killer Cells in Uveal Melanoma

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