Immune Selection of Hot-Spot β2<i>-Microglobulin</i> Gene Mutations, HLA-A2 Allospecificity Loss, and Antigen-Processing Machinery Component Down-Regulation in Melanoma Cells Derived from Recurrent Metastases following Immunotherapy

Chang, Chien‐Chung; Campoli, Michael; Restifo, Nicholas P.; Wang, Xinhui; Ferrone, Soldano

doi:10.4049/jimmunol.174.3.1462

Cited by 89 publications

(72 citation statements)

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“…Therefore, the elicited CTL response was spontaneous in nature as opposed to the response introduced by T cell-based immunotherapy. This is also reflected by the location of the identified ␤ 2 m gene mutation (TGC to TGG in exon 2), outside the mutational hot spot in exon 1, which in melanoma has been found mostly in patients exposed to T cell-based immunotherapy-related immune selective pressure (29). Whether this type of mutation will represent a common one among malignant cells exposed to spontaneous CTL immune selective pressure remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Defective Human Leukocyte Antigen Class I-associated Antigen Presentation Caused by a Novel β2-Microglobulin Loss-of-function in Melanoma Cells

Chang

Ogino

Mullins

et al. 2006

Journal of Biological Chemistry

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The major histocompatibility complex class I molecules consist of three subunits, the 45-kDa heavy chain, the 12-kDa ␤ 2 -microglobulin (␤ 2 m), and an ϳ8 -9-residue antigenic peptide. Without ␤ 2 m, the major histocompatibility complex class I molecules cannot assemble, thereby abolishing their transport to the cell membrane and the subsequent recognition by antigen-specific T cells. The human leukocyte antigen (HLA) 4 class I molecules, encoded by the genes located in the major histocompatibility complex, are composed of three subunits including a 45-kDa HLA class I heavy chain (HC), a 12-kDa ␤ 2 -microglobulin (␤ 2 m), and an ϳ8 -9-residue peptide (1). Expression of these molecules on the cell surface requires the stepwise assembly of HCs, ␤ 2 m, and peptides in the endoplasmic reticulum (ER) followed by the transport of the trimeric molecule to the plasma membrane. These processes are dependent on a functional antigen processing machinery (APM), which includes the proteasome subunits, the peptide transporters TAP1 and TAP2, and a number of ER-resident chaperons such as calnexin, calreticulin, ERp57, and tapasin (2, 3). ␤ 2 m plays an integral part in the assembly and transport of HLA class I molecules because it stabilizes the HC-␤ 2 m heterodimer through noncovalent protein-protein interactions, thereby allowing binding of endogenous antigenic peptides with the help of TAP and tapasin (4). As a result, the assembled HC-␤ 2 m-peptide trimeric complexes can travel to the cell surface, where they are recognized by HLA class I-restricted, antigen-specific cytotoxic T lymphocytes (CTLs).The lack of HLA class I molecule expression on the cell surface usually reflects defects in ␤ 2 m protein synthesis caused by mutations in the ␤ 2 m gene, as has been found mostly in malignant cells thus far (5). This abnormality renders tumor cells resistant to tumor antigenspecific CTLs and may have a negative impact on the elimination of tumor cells by host CTLs. The defects underlying ␤ 2 m loss have thus far been found to be structural in nature, involving lack of translation because of small deletions or point mutations in most cases and lack of transcription because of large deletions in a few cases (5). Because of a lack of ␤ 2 m expression, the resulting HLA class I loss cannot be corrected by interferon (IFN-␥), a cytokine that up-regulates the expression of most of the molecules participating in the assembly and transport of HLA class I molecules. On the other hand, a low level of HLA class I expression on cells usually reflects nonstructural defects in the APM components because this abnormality can be corrected by .In the present study, we have elucidated the mechanism underlying HLA class I down-regulation identified in a melanoma cell line and in the metastasis from which the cell line was derived (7). This HLA class I down-regulation phenotype cannot be corrected by IFN-␥ and was unexpectedly found to be caused by an abnormal full-length ␤ 2 m protein that can neither form stable complexes with HCs nor assist in...

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Section: Discussionmentioning

confidence: 99%

Defective Human Leukocyte Antigen Class I-associated Antigen Presentation Caused by a Novel β2-Microglobulin Loss-of-function in Melanoma Cells

Chang

Ogino

Mullins

et al. 2006

Journal of Biological Chemistry

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“…3 Immune recognition of melanoma by T cells can be abrogated completely in case the tumor irreversibly looses its MHC class I expression, as it has repeatedly been detected in tumors of melanoma patients after immunotherapy. [48][49][50] In this situation, NK cells might become particular important for melanoma immune surveillance. We demonstrated that melanoma cells were lysed by NK cells in an NKG2D-FIGURE 6 -Impact of IFN-g on the recognition of melanoma cells by activated primary NK cells.…”

Section: Discussionmentioning

confidence: 99%

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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“…Mel249 cells were characterized by a frameshift mutation consisting of a 2-bp microdeletion in codon 62 of exon II of the b2m gene. The majority of b2m gene mutations detected in different tumor types thus far is concentrated in exon I and exon II, but a repetitive sequence of CT dinucleotides in exon I has been described as a mutational hotspot region of the b2m gene (17,19).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, total loss of HLA class I expression in melanoma is mainly due to mutations affecting the b2m gene (8)(9)(10)13), mapping to chromosome region 15q21 (14). Interestingly, such alterations have repeatedly been detected in tumors of melanoma patients after immunotherapy (15)(16)(17).…”

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confidence: 99%

“…Analysis of the molecular mechanisms of h2m deficiency in different melanoma cell lines revealed that, in some cases, large deletions within the b2m gene prevented transcription whereas, in the majority, a mutated nonfunctional gene product was expressed originating from nucleotide microdeletions or transitions in exons I and II of the b2m gene (16)(17)(18). Interestingly, the coincidence of two different b2m gene mutations within one melanoma cell line has never been described.…”

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The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

Paschen

Arens

Sucker

et al. 2006

Clinical Cancer Research

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Purpose:Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8 + Tcells, is known to be caused by mutations in the h2-microglobulin (b2m) gene. We asked whether abnormalities of chromosome 15, harboring the b2m gene on 15q21, in addition to b2m gene mutations, are causative for the HLA class I^negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the h2m-negative metastatic melanoma tissues of four different patients and analyzed them for b2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the b2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions.Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) b2m gene mutations.Melanoma cells can be effectively eradicated in vivo by the cytotoxic activity of HLA class I-restricted tumor antigenspecific CD8 + T cells as recently shown in clinical trials of adoptive T-cell transfer (1, 2). However, these studies also showed that adoptively transferred T cells infiltrating the metastasis not only act as cytotoxic immune effectors but also as immune editors (3, 4) selecting for tumor cell variants that escape immune surveillance by down-regulation of antigen expression (1). Besides antigen down-regulation, other properties of melanoma cells that interfere with T-cell effector function have been described, such as release of immunosuppressive cytokines (5, 6), release of Fas ligand-bearing microvesicles (7), and alterations in the surface presentation of HLA class I molecules (8-10).HLA class I molecules are heterodimeric noncovalently associated complexes consisting of the constant h2-microglobulin (h2m) light chain and the variable HLA heavy a chain. Irreversible alterations in the HLA class I phenotype of melanoma cells, such as loss of a single HLA allele, an HLA locus, or an HLA haplotype, are generally caused by

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Immune Selection of Hot-Spot β2-Microglobulin Gene Mutations, HLA-A2 Allospecificity Loss, and Antigen-Processing Machinery Component Down-Regulation in Melanoma Cells Derived from Recurrent Metastases following Immunotherapy

Cited by 89 publications

References 40 publications

Defective Human Leukocyte Antigen Class I-associated Antigen Presentation Caused by a Novel β2-Microglobulin Loss-of-function in Melanoma Cells

Defective Human Leukocyte Antigen Class I-associated Antigen Presentation Caused by a Novel β2-Microglobulin Loss-of-function in Melanoma Cells

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

The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

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