Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy
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Publication date
2024-02-12
Authors
Wienke, Judith
Visser, Lindy L
Kholosy, Waleed M
Keller, Kaylee M
Barisa, Marta
Poon, Evon
Munnings-Tomes, Sophie
Himsworth, Courtney
Calton, Elizabeth
Rodriguez, Ana
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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-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
B7-H1 Antigen, Child, Humans, Immunotherapy, Neoplasm Recurrence, Local, Neuroblastoma/drug therapy, Receptors, Immunologic/genetics, Sequence Analysis, RNA, Pediatric oncology, Neuroblastoma, Immune checkpoint inhibition, immune evasion, immunotherapy, PD-L1, tumor microenvironment, TIGIT, PD-1, NECTIN2, Oncology, Cancer Research, Journal Article, Research Support, Non-U.S. Gov't
Citation
Wienke, J, Visser, L L, Kholosy, W M, Keller, K M, Barisa, M, Poon, E, Munnings-Tomes, S, Himsworth, C, Calton, E, Rodriguez, A, Bernardi, R, van den Ham, F, van Hooff, S R, Matser, Y A H, Tas, M L, Langenberg, K P S, Lijnzaad, P, Borst, A L, Zappa, E, Bergsma, F J, Strijker, J G M, Verhoeven, B M, Mei, S, Kramdi, A, Restuadi, R, Sanchez-Bernabeu, A, Cornel, A M, Holstege, F C P, Gray, J C, Tytgat, G A M, Scheijde-Vermeulen, M A, Wijnen, M H W A, Dierselhuis, M P, Straathof, K, Behjati, S, Wu, W, Heck, A J R, Koster, J, Nierkens, S, Janoueix-Lerosey, I, de Krijger, R R, Baryawno, N, Chesler, L, Anderson, J, Caron, H N, Margaritis, T, van Noesel, M M & Molenaar, J J 2024, 'Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy', Cancer Cell, vol. 42, no. 2, pp. 283-300.e8. https://doi.org/10.1016/j.ccell.2023.12.008