Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers
The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory...
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1265469/full |
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| author | Wan Ching Lim Wan Ching Lim Wan Ching Lim Maria Eugenia Marques Da Costa Karine Godefroy Eric Jacquet Loren Gragert Windy Rondof Windy Rondof Antonin Marchais Antonin Marchais Naima Nhiri Davide Dalfovo Mathias Viard Mathias Viard Nizar Labaied Asif M. Khan Philippe Dessen Alessandro Romanel Claudia Pasqualini Claudia Pasqualini Gudrun Schleiermacher Mary Carrington Mary Carrington Mary Carrington Laurence Zitvogel Jean-Yves Scoazec Birgit Geoerger Birgit Geoerger Jerome Salmon |
| author_facet | Wan Ching Lim Wan Ching Lim Wan Ching Lim Maria Eugenia Marques Da Costa Karine Godefroy Eric Jacquet Loren Gragert Windy Rondof Windy Rondof Antonin Marchais Antonin Marchais Naima Nhiri Davide Dalfovo Mathias Viard Mathias Viard Nizar Labaied Asif M. Khan Philippe Dessen Alessandro Romanel Claudia Pasqualini Claudia Pasqualini Gudrun Schleiermacher Mary Carrington Mary Carrington Mary Carrington Laurence Zitvogel Jean-Yves Scoazec Birgit Geoerger Birgit Geoerger Jerome Salmon |
| author_sort | Wan Ching Lim |
| collection | DOAJ |
| description | The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers. |
| first_indexed | 2024-03-08T12:24:29Z |
| format | Article |
| id | doaj.art-b7bf7991e0734276842ecffd32168c0d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T12:24:29Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b7bf7991e0734276842ecffd32168c0d2024-01-22T10:57:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011410.3389/fimmu.2023.12654691265469Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancersWan Ching Lim0Wan Ching Lim1Wan Ching Lim2Maria Eugenia Marques Da Costa3Karine Godefroy4Eric Jacquet5Loren Gragert6Windy Rondof7Windy Rondof8Antonin Marchais9Antonin Marchais10Naima Nhiri11Davide Dalfovo12Mathias Viard13Mathias Viard14Nizar Labaied15Asif M. Khan16Philippe Dessen17Alessandro Romanel18Claudia Pasqualini19Claudia Pasqualini20Gudrun Schleiermacher21Mary Carrington22Mary Carrington23Mary Carrington24Laurence Zitvogel25Jean-Yves Scoazec26Birgit Geoerger27Birgit Geoerger28Jerome Salmon29INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceBioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceSchool of Data Sciences, Perdana University, Kuala Lumpur, MalaysiaINSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceDepartment of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceInstitut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Saclay, Gif-sur-Yvette, FranceDepartment of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United StatesINSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceBioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceINSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceBioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceInstitut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Saclay, Gif-sur-Yvette, FranceDepartment of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, ItalyFrederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLaboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United StatesDepartment of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceSchool of Data Sciences, Perdana University, Kuala Lumpur, MalaysiaBioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceDepartment of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, ItalyINSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France0Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France1INSERM U830, Recherche Translationnelle en Oncologie Pédiatrique (RTOP), and SIREDO Oncology Center (Care, Innovation and Research for Children and AYA with Cancer), PSL Research University, Institut Curie, Paris, FranceFrederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLaboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States2Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA, United StatesINSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceDepartment of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceINSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France0Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceINSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, FranceThe human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1265469/fullpediatric cancersrefractory and recurrent solid tumorsimmunogeneticsHLAtumor immunityimmunotherapy |
| spellingShingle | Wan Ching Lim Wan Ching Lim Wan Ching Lim Maria Eugenia Marques Da Costa Karine Godefroy Eric Jacquet Loren Gragert Windy Rondof Windy Rondof Antonin Marchais Antonin Marchais Naima Nhiri Davide Dalfovo Mathias Viard Mathias Viard Nizar Labaied Asif M. Khan Philippe Dessen Alessandro Romanel Claudia Pasqualini Claudia Pasqualini Gudrun Schleiermacher Mary Carrington Mary Carrington Mary Carrington Laurence Zitvogel Jean-Yves Scoazec Birgit Geoerger Birgit Geoerger Jerome Salmon Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers Frontiers in Immunology pediatric cancers refractory and recurrent solid tumors immunogenetics HLA tumor immunity immunotherapy |
| title | Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers |
| title_full | Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers |
| title_fullStr | Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers |
| title_full_unstemmed | Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers |
| title_short | Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers |
| title_sort | divergent hla variations and heterogeneous expression but recurrent hla loss of heterozygosity and common hla b and tap transcriptional silencing across advanced pediatric solid cancers |
| topic | pediatric cancers refractory and recurrent solid tumors immunogenetics HLA tumor immunity immunotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1265469/full |
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