PMID- 38318504 OWN - NLM STAT- MEDLINE DCOM- 20240207 LR - 20240322 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - 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. PG - 1265469 LID - 10.3389/fimmu.2023.1265469 [doi] LID - 1265469 AB - 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. CI - Copyright (c) 2024 Lim, Marques Da Costa, Godefroy, Jacquet, Gragert, Rondof, Marchais, Nhiri, Dalfovo, Viard, Labaied, Khan, Dessen, Romanel, Pasqualini, Schleiermacher, Carrington, Zitvogel, Scoazec, Geoerger and Salmon. FAU - Lim, Wan Ching AU - Lim WC AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. AD - Bioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. AD - School of Data Sciences, Perdana University, Kuala Lumpur, Malaysia. FAU - Marques Da Costa, Maria Eugenia AU - Marques Da Costa ME AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Godefroy, Karine AU - Godefroy K AD - Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Jacquet, Eric AU - Jacquet E AD - Institut de Chimie des Substances Naturelles, CNRS UPR2301, Universite Paris-Saclay, Gif-sur-Yvette, France. FAU - Gragert, Loren AU - Gragert L AD - Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States. FAU - Rondof, Windy AU - Rondof W AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. AD - Bioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Marchais, Antonin AU - Marchais A AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. AD - Bioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Nhiri, Naima AU - Nhiri N AD - Institut de Chimie des Substances Naturelles, CNRS UPR2301, Universite Paris-Saclay, Gif-sur-Yvette, France. FAU - Dalfovo, Davide AU - Dalfovo D AD - Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. FAU - Viard, Mathias AU - Viard M AD - Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States. AD - Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States. FAU - Labaied, Nizar AU - Labaied N AD - Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Khan, Asif M AU - Khan AM AD - School of Data Sciences, Perdana University, Kuala Lumpur, Malaysia. FAU - Dessen, Philippe AU - Dessen P AD - Bioinformatics Platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Romanel, Alessandro AU - Romanel A AD - Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. FAU - Pasqualini, Claudia AU - Pasqualini C AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. AD - Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Schleiermacher, Gudrun AU - Schleiermacher G AD - INSERM U830, Recherche Translationnelle en Oncologie Pediatrique (RTOP), and SIREDO Oncology Center (Care, Innovation and Research for Children and AYA with Cancer), PSL Research University, Institut Curie, Paris, France. FAU - Carrington, Mary AU - Carrington M AD - Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States. AD - Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States. AD - Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA, United States. FAU - Zitvogel, Laurence AU - Zitvogel L AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Scoazec, Jean-Yves AU - Scoazec JY AD - Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Geoerger, Birgit AU - Geoerger B AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. AD - Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. FAU - Salmon, Jerome AU - Salmon J AD - INSERM U1015, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France. LA - eng GR - 75N91019D00024/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20240122 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Histocompatibility Antigens Class II) RN - 0 (HLA Antigens) RN - 0 (HLA-B Antigens) SB - IM MH - Adolescent MH - Child MH - Humans MH - Antigen Presentation MH - *Glioma MH - Histocompatibility Antigens Class I/genetics MH - Histocompatibility Antigens Class II/genetics MH - HLA Antigens/genetics MH - HLA-B Antigens/genetics MH - *Sarcoma, Ewing/genetics MH - Animals MH - Young Adult PMC - PMC10839790 OTO - NOTNLM OT - HLA OT - immunogenetics OT - immunotherapy OT - pediatric cancers OT - refractory and recurrent solid tumors OT - tumor immunity COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. EDAT- 2024/02/06 06:42 MHDA- 2024/02/07 06:43 PMCR- 2023/01/01 CRDT- 2024/02/06 04:01 PHST- 2023/07/22 00:00 [received] PHST- 2023/11/06 00:00 [accepted] PHST- 2024/02/07 06:43 [medline] PHST- 2024/02/06 06:42 [pubmed] PHST- 2024/02/06 04:01 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1265469 [doi] PST - epublish SO - Front Immunol. 2024 Jan 22;14:1265469. doi: 10.3389/fimmu.2023.1265469. eCollection 2023.