Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy
Author:
Wienke JudithORCID, Visser Lindy L., Kholosy Waleed M., Keller Kaylee M., Barisa Marta, Munnings-Tomes Sophie, Carlton Elizabeth, Poon Evon, Rodriguez Ana, Bernardi Ronald, van den Ham Femke, van Hooff Sander R., Matser Yvette A.H., Tas Michelle L., Langenberg Karin P.S., Lijnzaad Philip, Strijker Josephine G.M., Sanchez-Bernabeu Alvaro, Cornel Annelisa M., Holstege Frank C.P., Gray Juliet, Tytgat Lieve A.M., de Krijger Ronald R., Scheijde-Vermeulen Marijn A., Wijnen Marc H.W.A., Dierselhuis Miranda, Straathof Karin, Behjati Sam, Wu Wei, Heck Albert J.R., Koster Jan, Nierkens Stefan, Chesler Louis, Anderson John, Caron Hubert N., Margaritis Thanasis, van Noesel Max M., Molenaar Jan J.
Abstract
ABSTRACTPediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. As novel and improved immunotherapies may fill this need, we dissected the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 25 tumors (10 pre- and 15 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas were infiltrated by NK, T and B cells, and immunosuppressive myeloid populations. NK cells showed reduced cytotoxicity and T cells had a dysfunctional profile. Interaction analysis revealed a vast immunoregulatory network and identified NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduced neuroblastoma growth, with complete responses in vivo. Moreover, addition of TIGIT blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model significantly improved survival. Concluding, our integrative analysis of neuroblastoma’s vast immunoregulatory network provides novel targets and a rationale for immunotherapeutic combination strategies.
Publisher
Cold Spring Harbor Laboratory
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