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

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 BergsmaJosephine 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

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	283-300.e8
Journal	Cancer Cell
Volume	42
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2023.12.008
Publication status	Published - 12 Feb 2024

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

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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., ... 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, 42(2), 283-300.e8. https://doi.org/10.1016/j.ccell.2023.12.008

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = feb,

day = "12",

doi = "10.1016/j.ccell.2023.12.008",

language = "English",

volume = "42",

pages = "283--300.e8",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

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Wienke, J, Visser, LL, Kholosy, WM, Keller, KM, Barisa, M, Poon, E, Munnings-Tomes, S, Himsworth, C, Calton, E, Rodriguez, A, Bernardi, R, van den Ham, F, van Hooff, SR, Matser, YAH, Tas, ML, Langenberg, KPS, Lijnzaad, P, Borst, AL, Zappa, E, Bergsma, FJ, Strijker, JGM, Verhoeven, BM, Mei, S, Kramdi, A, Restuadi, R, Sanchez-Bernabeu, A, Cornel, AM, Holstege, FCP, Gray, JC, Tytgat, GAM, Scheijde-Vermeulen, MA, Wijnen, MHWA, Dierselhuis, MP, Straathof, K, Behjati, S, Wu, W, Heck, AJR, Koster, J, Nierkens, S, Janoueix-Lerosey, I, de Krijger, RR, Baryawno, N, Chesler, L, Anderson, J, Caron, HN, Margaritis, T, van Noesel, MM & Molenaar, JJ 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

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

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 -

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

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