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

Judith Wienke(Princess Máxima Center), Lindy L. Visser(Princess Máxima Center), Waleed M. Kholosy(Princess Máxima Center), Kaylee M. Keller(Princess Máxima Center), Marta Barisa(University College London), Evon Poon(Institute of Cancer Research), Sophie Munnings-Tomes(University College London), Courtney Himsworth(Great Ormond Street Hospital), Elizabeth Calton(Institute of Cancer Research), Ana Isabel Enríquez Rodríguez(Roche (Switzerland)), Ronald J. Bernardi(La Roche College), Femke van den Ham(Princess Máxima Center), Sander R. van Hooff(Princess Máxima Center), Yvette A.H. Matser(Princess Máxima Center), Michelle L. Tas(Princess Máxima Center), Karin P.S. Langenberg(Princess Máxima Center), Philip Lijnzaad(Princess Máxima Center), Anne L. Borst(Princess Máxima Center), Elisa Zappa(Princess Máxima Center), Francisca J Bergsma(Princess Máxima Center), Josephine G. M. Strijker(Princess Máxima Center), Bronte Manouk Verhoeven(Karolinska Institutet), Shenglin Mei(Harvard University), Amira Kramdi, Restuadi Restuadi, Álvaro Sánchez-Bernabéu, Annelisa M. Cornel, Frank C. P. Holstege(Princess Máxima Center), Juliet C. Gray(University of Southampton), Godelieve A.M. Tytgat(Princess Máxima Center), Marijn A. Scheijde‐Vermeulen(Princess Máxima Center), Marc H.W.A. Wijnen(Princess Máxima Center), Miranda P. Dierselhuis(Princess Máxima Center), Karin Straathof(CRUK Lung Cancer Centre of Excellence), Sam Behjati, Wei Wu, Albert J. R. Heck, Jan Koster(University of Amsterdam), Stefan Nierkens, Isabelle Janoueix‐Lerosey, Ronald R. de Krijger, Ninib Baryawno(Karolinska Institutet), Louis Chesler(Institute of Cancer Research), John Anderson, Hubert Caron(Roche (Switzerland)), Thanasis Margaritis(Princess Máxima Center), Max M. van Noesel, Jan J. Molenaar
Cancer Cell
January 4, 2024
10.1016/j.ccell.2023.12.008
Cited by 92Open Access
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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-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.

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