A lineage-specific methylation pattern controls the transcription of the polycistronic mRNA coding MELOE melanoma antigens

Chalopin, Benjamin; Florenceau, Laetitia; Fradin, Delphine; Labarrière, Nathalie; Moreau-Aubry, Agnès

doi:10.1097/cmr.0000000000000167

Cited by 5 publications

(5 citation statements)

References 12 publications

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“…This RNA probably belongs to the family of long intronic non coding RNA (lncRNA) [ 4 ] since it shares many of their features: it is located in the intron of HDAC4 in antisense direction, it is capped and polyadenylated and contains no long ORF but multiple short ORFs (< 100 aa) and is transcribed in a tissue specific manner i.e. the melanocytic lineage [ 5 , 6 ]. Despite their denomination as « non coding » RNAs, it was shown that many lncRNAs can in fact be translated into short polypeptides [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens

et al. 2016

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MELOE-1 and MELOE-2, two highly specific melanoma antigens involved in T cell immunosurveillance are produced by IRES-dependent translation of the long « non coding » and polycistronic RNA, meloe. In the present study, we document the expression of an additional ORF, MELOE-3, located in the 5′ region of meloe. Data from in vitro translation experiments and transfection of melanoma cells with bicistronic vectors documented that MELOE-3 is exclusively translated by the classical cap-dependent pathway. Using a sensitive tandem mass spectrometry technique, we detected the presence of MELOE-3 in total lysates of both melanoma cells and normal melanocytes. This contrasts with our previous observation of the melanoma-restricted expression of MELOE-1 and MELOE-2. Furthermore, in vitro stimulation of PBMC from 6 healthy donors with overlapping peptides from MELOE-1 or MELOE-3 revealed a very scarce MELOE-3 specific T cell repertoire as compared to the abundant repertoire observed against MELOE-1. The poor immunogenicity of MELOE-3 and its expression in melanocytes is consistent with an immune tolerance towards a physiologically expressed protein. In contrast, melanoma-restricted expression of IRES-dependent MELOE-1 may explain its high immunogenicity. In conclusion, within the MELOE family, IRES-dependent antigens represent the best T cell targets for immunotherapy of melanoma.

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Section: Introductionmentioning

confidence: 99%

IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens

et al. 2016

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“…Epigenetic dysregulation of the cancer genome leads to the expression of genomic regions that are generally silent ( 51 ). For example, it was shown that the promoter of the polycistronic transcript meloe, which encodes the MELOE-1 and MELOE-2 cancer-specific peptides, is hypomethylated in melanoma ( 52 ). HERV sequences cover about 8% of the genome and can become reactivated in cancer ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Microproteins encoded by noncanonical ORFs are a major source of tumor-specific antigens in a liver cancer patient meta-cohort

Camarena,

Theunissen,

Ruiz

et al. 2024

Sci. Adv.

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The expression of tumor-specific antigens during cancer progression can trigger an immune response against the tumor. Here, we investigate if microproteins encoded by noncanonical open reading frames (ncORFs) are a relevant source of tumor-specific antigens. We analyze RNA sequencing data from 117 hepatocellular carcinoma (HCC) tumors and matched healthy tissue together with ribosome profiling and immunopeptidomics data. Combining human leukocyte antigen–epitope binding predictions and experimental validation experiments, we conclude that around 40% of the tumor-specific antigens in HCC are likely to be derived from ncORFs, including two peptides that can trigger an immune response in humanized mice. We identify a subset of 33 tumor-specific long noncoding RNAs expressing novel cancer antigens shared by more than 10% of the HCC samples analyzed, which, when combined, cover a large proportion of the patients. The results of the study open avenues for extending the range of anticancer vaccines.

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“…Epigenetic dysregulation of the cancer genome leads to the expression of genomic regions that are generally silent 53 . For example, it was shown that the promoter of the polycistronic transcript meloe, which encodes the MELOE-1 and MELOE-2 cancer-specific peptides, is hypomethylated in melanoma 54 . HERV sequences cover about 8% of the genome and can become reactivated in cancer 55 .…”

Section: Discussionmentioning

confidence: 99%

Non-canonical ORFs are an important source of tumor-specific antigens in a liver cancer meta-cohort

Camarena,

Theunissen,

Ruiz

et al. 2023

Preprint

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The expression of tumor-specific antigens during cancer progression can trigger an immune response against the tumor. Antigens that have been used as cancer vaccines are those originated by non- synonymous mutations and those derived from cancer/testis antigens. However, the first class is predominantly patient-specific, preventing the development of therapies than can benefit multiple patients, and the second one offers a limited set of actionable targets. A possible alternative is the use of peptides derived from non-canonical ORFs (ncORFs). While many ncORFs have been shown to be translated in cancer cells, their tumor-specificity and patient distribution remains to be determined. Here we analyze RNA sequencing data 117 hepatocellular carcinoma (HCC) tumors and matched healthy tissue, together with ribosome profiling data from an additional 10 HCC tumors, to answer these open questions. Combining HLA-epitope binding predictions and experimental validation experiments we conclude that around 40% of the tumor-specific antigens in HCC are likely to be derived from ncORFs in lncRNAs, including two peptides that can trigger an immune response in mice. We identify a subset of 33 tumor-specific lncRNAs expressing novel cancer antigens shared by more than 10% of the HCC analyzed, which could be combined to target a large proportion of the patients. The results of the study open new avenues for extending the range of anti-cancer vaccines.

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A lineage-specific methylation pattern controls the transcription of the polycistronic mRNA coding MELOE melanoma antigens

Cited by 5 publications

References 12 publications

IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens

IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens

Microproteins encoded by noncanonical ORFs are a major source of tumor-specific antigens in a liver cancer patient meta-cohort

Non-canonical ORFs are an important source of tumor-specific antigens in a liver cancer meta-cohort

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