TY - JOUR
T1 - Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy
AU - Wienke, Judith
AU - Visser, Lindy L
AU - Kholosy, Waleed M
AU - Keller, Kaylee M
AU - Barisa, Marta
AU - Poon, Evon
AU - Munnings-Tomes, Sophie
AU - Himsworth, Courtney
AU - Calton, Elizabeth
AU - Rodriguez, Ana
AU - Bernardi, Ronald
AU - van den Ham, Femke
AU - van Hooff, Sander R
AU - Matser, Yvette A H
AU - Tas, Michelle L
AU - Langenberg, Karin P S
AU - Lijnzaad, Philip
AU - Borst, Anne L
AU - Zappa, Elisa
AU - Bergsma, Francisca J
AU - Strijker, Josephine G M
AU - Verhoeven, Bronte M
AU - Mei, Shenglin
AU - Kramdi, Amira
AU - Restuadi, Restuadi
AU - Sanchez-Bernabeu, Alvaro
AU - Cornel, Annelisa M
AU - Holstege, Frank C P
AU - Gray, Juliet C
AU - Tytgat, Godelieve A M
AU - Scheijde-Vermeulen, Marijn A
AU - Wijnen, Marc H W A
AU - Dierselhuis, Miranda P
AU - Straathof, Karin
AU - Behjati, Sam
AU - Wu, Wei
AU - Heck, Albert J R
AU - Koster, Jan
AU - Nierkens, Stefan
AU - Janoueix-Lerosey, Isabelle
AU - de Krijger, Ronald R
AU - Baryawno, Ninib
AU - Chesler, Louis
AU - Anderson, John
AU - Caron, Hubert N
AU - Margaritis, Thanasis
AU - van Noesel, Max M
AU - Molenaar, Jan J
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2024/2/12
Y1 - 2024/2/12
N2 - 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.
AB - 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.
KW - B7-H1 Antigen
KW - Child
KW - Humans
KW - Immunotherapy
KW - Neoplasm Recurrence, Local
KW - Neuroblastoma/drug therapy
KW - Receptors, Immunologic/genetics
KW - Sequence Analysis, RNA
KW - Pediatric oncology
KW - Neuroblastoma
KW - Immune checkpoint inhibition
KW - immune evasion
KW - immunotherapy
KW - PD-L1
KW - tumor microenvironment
KW - TIGIT
KW - PD-1
KW - NECTIN2
UR - http://www.scopus.com/inward/record.url?scp=85183999694&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2023.12.008
DO - 10.1016/j.ccell.2023.12.008
M3 - Article
C2 - 38181797
SN - 1535-6108
VL - 42
SP - 283-300.e8
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -