Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Paschen, Annette; Méndez, Rosa; Jiménez, Pilar; Sucker, Antje; Ruiz‐Cabello, Francisco; Song, Mingxia; Garrido, Federico; Schadendorf, Dirk

doi:10.1002/ijc.10906

Cited by 93 publications

(69 citation statements)

References 33 publications

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“…This could be attributed to immune response generated from intranasal immunization. Since tumor cells can escape immune surveillance [31][32][33][34] through immune suppression 35,36 , altered expression of MHC class I 37,38 , as well as generation of immune escape tumor variants 39,40 , specific growth rates eventually www.nature.com/scientificreports caught up with that of control groups (Figures 3c and d). Lastly, through tetramer analysis we demonstrate that to induce anti-tumor immunity via intranasal route, it is necessary that mRNA is delivered in a nanoparticle.…”

Section: Discussionmentioning

confidence: 99%

Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity

Phua

Staats

Nair

et al. 2015

Journal of Controlled Release

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Section: Discussionmentioning

confidence: 99%

Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity

Phua

Staats

Nair

et al. 2015

Journal of Controlled Release

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“…The negative impact of IFN-g on tumor cell killing by NKL cells was not because of an induction of inhibitory MHC class I molecules, as functional assays were performed with melanoma cells characterized by an irreversible loss of MHC class I expression. 25,26 In case of Ma-Mel-86b cells, we further excluded an up-regulation of the ligands LLT1 and E-cadherin/N-cadherin binding to the MHC class I-independent inhibitory receptors NKR-P1A 35 and KLRG1, 36,37 respectively. We could corroborate the impaired lysis of IFN-g-treated melanoma cells also with primary NK cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…To study the ligand profile of NKG2D on melanoma cells, we selected the cell lines Mel249, Ma-Mel-86a, Ma-Mel-86b and UKRV-Mel-02, a third well-characterized MHC class I-negative melanoma cell line, 25 for analysis. Surface expression of the ligands MICA, MICB, ULBP1, ULBP2 and ULBP3 was determined by flow cytometry.…”

Section: Nkg2dl Surface Expression On Melanoma Cells Is Decreased In mentioning

confidence: 99%

“…Loss of MHC class I expression, as it has been repeatedly observed during disease progression, 25,26 should render melanoma cells highly susceptible for killing by NK cells, but only in case where ligands of activating NK cell receptors are expressed on the target cells. Therefore, we studied NKG2DL expression by MHC class I-deficient melanoma cells, whose MHC class I-negative phenotype is due to mutations in the b2 microglobulin (b2m) gene.…”

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confidence: 98%

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Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

Schwinn

Vokhminova

Sucker

et al. 2009

Intl Journal of Cancer

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NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of ab CD81 T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-c (IFN-c) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-c treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-c treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-c-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-c, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells. ' 2008 Wiley-Liss, Inc.Key words: melanoma; MHC class I loss; natural killer cell; NKG2D; interferon-c Malignant melanoma is well characterized for its recognition by cytotoxic ab CD8 1 T lymphocytes (CTLs) that respond to tumorassociated peptide antigens presented in the complex with classical MHC class I surface molecules.1 Indeed, CTLs can eliminate metastatic tumors in melanoma patients, as demonstrated in different clinical trials of adoptive T cell transfer.2 The efficiency of tumor cell killing is determined by the strength of the antigen signal and co-stimulatory signals sensed by different activating receptors. Very recently, it was demonstrated that triggering of the co-stimulatory receptor NKG2D on CTLs strongly enhanced the T cells capacity to kill melanoma cells. 3Besides the importance of antigen-specific CTLs in immune surveillance of melanoma, one can assume that early detection and elimination of premalignant and malignant cutaneous melanocytes might be a major task of skin-resident innate NK cells and innate-like Vd1 gd T lymphocytes. 4 Both effectors are capable of preventing and inhibiting the growth of autologous human melanoma grafted into the skin of severe combined immunodeficient (SCID) mice.5 Interestingly, the receptor NKG2D is constitutively expressed on Vd1 gd T cells present in normal human sk...

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“…In the tumour host immune response, HLA-A,B,C assembles with B2M in the endoplasmic reticulum (Momburg and Koch, 1989;. Loss of these class 1 antigens is associated with decreased histological differentiation in colon cancer (Gattoni-Celli et al, 1992), as well as increased malignancy in a number of neoplasms, including B-cell lymphoma (Moller et al, 1987) and melanoma (Paschen et al, 2003). Interestingly, loss of the native HLA-A,B,C/B2M complex appears to be sporadic in nature; in some cases, the loss is localised to certain portions of the tumour, whereas in others, loss of B2M is evident across the entire tumour (Momburg and Koch, 1989).…”

Section: Discussionmentioning

confidence: 99%

β2microglobulin mRNA expression levels are prognostic for lymph node metastasis in colorectal cancer patients

et al. 2008

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Colorectal cancer (CRC) is the fourth most common non-cutaneous malignancy in the United States and the second most frequent cause of cancer-related death. One of the most important determinants of CRC survival is lymph node metastasis. To determine whether molecular markers might be prognostic for lymph node metastases, we measured by quantitative real-time RT -PCR the expression levels of 15 cancer-associated genes in formalin-fixed paraffin-embedded primary tissues derived from stage I -IV CRC patients with (n ¼ 20) and without (n ¼ 18) nodal metastases. Using the mean of the 15 genes as an internal reference control, we observed that low expression of b 2 microglobulin (B2M) was a strong prognostic indicator of lymph node metastases (area under the curve (AUC) ¼ 0.85; 95% confidence interval (CI) ¼ 0.69 -0.94). We also observed that the expression ratio of B2M/Spint2 had the highest prognostic accuracy (AUC ¼ 0.87; 95% CI ¼ 0.71 -0.96) of all potential two-gene combinations. Expression values of Spint2 correlated with the mean of the entire gene set at an R 2 value of 0.97, providing evidence that Spint2 serves not as an independent prognostic gene, but rather as a reliable reference control gene. These studies are the first to demonstrate a prognostic role of B2M at the mRNA level and suggest that low B2M expression levels might be useful for identifying patients with lymph node metastasis and/or poor survival.

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Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Cited by 93 publications

References 33 publications

Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity

Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

β2microglobulin mRNA expression levels are prognostic for lymph node metastasis in colorectal cancer patients

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