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

Judith Wienke; Lindy L Visser; Waleed M Kholosy; Kaylee M Keller; Marta Barisa; Evon Poon; Sophie Munnings-Tomes; Courtney Himsworth; Elizabeth Calton; Ana Rodriguez; Ronald Bernardi; Femke van den Ham; Sander R van Hooff; Yvette A H Matser; Michelle L Tas; Karin P S Langenberg; Philip Lijnzaad; Anne L Borst; Elisa Zappa; Francisca J Bergsma; Josephine G M Strijker; Bronte M Verhoeven; Shenglin Mei; Amira Kramdi; Restuadi Restuadi; Alvaro Sanchez-Bernabeu; Annelisa M Cornel; Frank C P Holstege; Juliet C Gray; Godelieve A M Tytgat; Marijn A Scheijde-Vermeulen; Marc H W A Wijnen; Miranda P Dierselhuis; Karin Straathof; Sam Behjati; Wei Wu; Albert J R Heck; Jan Koster; Stefan Nierkens; Isabelle Janoueix-Lerosey; Ronald R de Krijger; Ninib Baryawno; Louis Chesler; John Anderson; Hubert N Caron; Thanasis Margaritis; Max M van Noesel; Jan J Molenaar

doi:10.1016/j.ccell.2023.12.008

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

Cancer Cell. 2024 Feb 12;42(2):283-300.e8. doi: 10.1016/j.ccell.2023.12.008. Epub 2024 Jan 4.

Authors

Judith Wienke¹, Lindy L Visser², Waleed M Kholosy², Kaylee M Keller², Marta Barisa³, Evon Poon⁴, Sophie Munnings-Tomes³, Courtney Himsworth³, Elizabeth Calton⁴, Ana Rodriguez⁵, Ronald Bernardi⁶, Femke van den Ham², Sander R van Hooff², Yvette A H Matser², Michelle L Tas², Karin P S Langenberg², Philip Lijnzaad², Anne L Borst², Elisa Zappa², Francisca J Bergsma², Josephine G M Strijker², Bronte M Verhoeven⁷, Shenglin Mei⁸, Amira Kramdi⁹, Restuadi Restuadi¹⁰, Alvaro Sanchez-Bernabeu¹¹, Annelisa M Cornel¹², Frank C P Holstege², Juliet C Gray¹³, Godelieve A M Tytgat², Marijn A Scheijde-Vermeulen², Marc H W A Wijnen², Miranda P Dierselhuis², Karin Straathof¹⁴, Sam Behjati¹⁵, Wei Wu¹⁶, Albert J R Heck¹¹, Jan Koster¹⁷, Stefan Nierkens¹², Isabelle Janoueix-Lerosey⁹, Ronald R de Krijger¹⁸, Ninib Baryawno⁷, Louis Chesler⁴, John Anderson¹⁹, Hubert N Caron⁵, Thanasis Margaritis², Max M van Noesel²⁰, Jan J Molenaar²¹

Affiliations

¹ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. Electronic address: j.wienke-4@prinsesmaximacentrum.nl.
² Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
³ Cancer Section, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
⁴ Division of Clinical Studies, The Institute of Cancer Research, London, UK.
⁵ Hoffman-La Roche, Basel, Switzerland.
⁶ Genentech, A Member of the Roche Group, South San Francisco, CA, USA.
⁷ Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
¹³ Centre for Cancer Immunology, University of Southampton, Southampton, UK.
¹⁴ University College London (UCL) Great Ormond Street Institute of Child Health, London, UK; UCL Cancer Institute, London, UK.
¹⁵ Wellcome Sanger Institute, Hinxton, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK.
¹⁶ 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.
¹⁷ Amsterdam UMC location University of Amsterdam, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands.
¹⁸ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁹ 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.
²⁰ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Division Imaging & Cancer, University Medical Center Utrecht, Utrecht, the Netherlands.
²¹ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.

Abstract

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.

Keywords: Immune checkpoint inhibition; NECTIN2; Neuroblastoma; PD-1; PD-L1; Pediatric oncology; TIGIT; immune evasion; immunotherapy; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen*
Child
Humans
Immunotherapy
Neoplasm Recurrence, Local
Neuroblastoma* / drug therapy
Neuroblastoma* / genetics
Receptors, Immunologic / genetics
Sequence Analysis, RNA

Substances

B7-H1 Antigen
Receptors, Immunologic
TIGIT protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding