Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy.

Autor:	Wienke J; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. Electronic address: j.wienke-4@prinsesmaximacentrum.nl., Visser LL; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Kholosy WM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Keller KM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Barisa M; Cancer Section, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK., Poon E; Division of Clinical Studies, The Institute of Cancer Research, London, UK., Munnings-Tomes S; Cancer Section, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK., Himsworth C; Cancer Section, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK., Calton E; Division of Clinical Studies, The Institute of Cancer Research, London, UK., Rodriguez A; Hoffman-La Roche, Basel, Switzerland., Bernardi R; Genentech, A Member of the Roche Group, South San Francisco, CA, USA., van den Ham F; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., van Hooff SR; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Matser YAH; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Tas ML; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Langenberg KPS; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Lijnzaad P; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Borst AL; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Zappa E; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Bergsma FJ; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Strijker JGM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Verhoeven BM; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Mei S; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA., Kramdi A; Institut Curie, Inserm U830, PSL Research University, Diversity and Plasticity of Childhood Tumors Lab, Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France., Restuadi R; Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK; NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK., Sanchez-Bernabeu A; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Netherlands Proteomics Centre, Utrecht University, Utrecht, the Netherlands., Cornel AM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Holstege FCP; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Gray JC; Centre for Cancer Immunology, University of Southampton, Southampton, UK., Tytgat GAM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Scheijde-Vermeulen MA; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Wijnen MHWA; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Dierselhuis MP; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Straathof K; University College London (UCL) Great Ormond Street Institute of Child Health, London, UK; UCL Cancer Institute, London, UK., Behjati S; Wellcome Sanger Institute, Hinxton, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK., Wu W; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Netherlands Proteomics Centre, Utrecht University, Utrecht, the Netherlands; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Department of Pharmacy, National University of Singapore, Singapore, Singapore., Heck AJR; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Netherlands Proteomics Centre, Utrecht University, Utrecht, the Netherlands., Koster J; Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands., Nierkens S; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., Janoueix-Lerosey I; Institut Curie, Inserm U830, PSL Research University, Diversity and Plasticity of Childhood Tumors Lab, Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France., de Krijger RR; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands., Baryawno N; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Chesler L; Division of Clinical Studies, The Institute of Cancer Research, London, UK., Anderson J; Cancer Section, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, England, UK., Caron HN; Hoffman-La Roche, Basel, Switzerland., Margaritis T; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., van Noesel MM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Division Imaging & Cancer, University Medical Center Utrecht, Utrecht, the Netherlands., Molenaar JJ; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2024 Feb 12; Vol. 42 (2), pp. 283-300.e8. Date of Electronic Publication: 2024 Jan 04.
DOI:	10.1016/j.ccell.2023.12.008
Abstrakt:	Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALK F1174L /MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies. Competing Interests: Declaration of interests H.C., A.R., and R.B. are employed at Hoffman-La Roche. R.B. also is an employee of Genentech, a member of the Roche Group. J.A. has founder shares in Autolus Ltd. J.A. and L.C. have received research funding from Roche for in vivo work. J.M. has received research funding from Roche for in vitro work. J.C.G is a member of a DMC for trials sponsored by YmAbs Therapeutics and University of Birmingham, and has had consulting roles for EUSA Pharma, YmAbs Therapeutics, Celgene, Servier and Norgine. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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