Combined Blockade of TIGIT and PD-L1 Enhances Anti-Neuroblastoma Efficacy of GD2-Directed Immunotherapy with Dinutuximab Beta
Author:
Siebert Nikolai1ORCID, Zumpe Maxi1ORCID, Schwencke Christian Heinrich1, Biskupski Simon1, Troschke-Meurer Sascha1ORCID, Leopold Justus1, Zikoridse Alexander1, Lode Holger N.1
Affiliation:
1. Department of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, Germany
Abstract
Immunotherapies against high-risk neuroblastoma (NB), using the anti-GD2 antibody (Ab) dinutuximab beta (DB), significantly improved patient survival. Ab-dependent cellular cytotoxicity (ADCC) is one of the main mechanisms of action and it is primarily mediated by NK cells. To further improve antitumor efficacy, we investigated here a combinatorial immunotherapy with DB and the double immune checkpoint blockade of T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death ligand-1 (PD-L1). The effects of ADCC, mediated by DB against NB cells on NK-cell activity, and the expression of TIGIT and CD226 and their ligands CD112 and CD155, as well as of PD-1 and PD-L1 on NB and effector cells, were investigated using flow cytometry. ADCC was assessed with a calcein-AM-based cytotoxicity assay. The efficacy of a combinatorial immunotherapy with DB, given as a long-term treatment, and the double immune checkpoint blockade of TIGIT and PD-L1 was shown using a resistant murine model of NB, followed by an analysis of the tumor tissue. We detected both TIGIT ligands, CD112 and CD155, on all NB cell lines analyzed. Although ADCC by DB resulted in a strong activation of NK cells leading to an effective tumor cell lysis, a remarkable induction of PD-L1 expression on NB cells, and of TIGIT and PD-1 on effector cells, especially on NK cells, was observed. Additional anti-TIGIT or anti-PD-L1 treatments effectively inhibited tumor growth and improved survival of the mice treated with DB. The superior antitumor effects were observed in the “DB + double immune checkpoint blockade” group, showing an almost complete eradication of the tumors and the highest OS, even under resistant conditions. An analysis of tumor tissue revealed both TIGIT and TIGIT ligand expression on myeloid-derived suppressor cells (MDSCs), suggesting additional mechanisms of protumoral effects in NB. Our data show that the targeting of TIGIT and PD-L1 significantly improves the antitumor efficacy of anti-GD2 immunotherapy, with DB presenting a new effective combinatorial treatment strategy against high-risk tumors.
Funder
Hector Stiftungen, Germany University Medicine Greifswald Deutsche Forschungsgemeinschaft F. Hoffmann-La Roche Ltd.
Subject
Cancer Research,Oncology
Reference28 articles.
1. Paraboschi, I., Privitera, L., Kramer-Marek, G., Anderson, J., and Giuliani, S. (2021). Novel Treatments and Technologies Applied to the Cure of Neuroblastoma. Children, 8. 2. Ladenstein, R., Pötschger, U., Valteau-Couanet, D., Luksch, R., Castel, V., Ash, S., Laureys, G., Brock, P., Michon, J.M., and Owens, C. (2020). Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers, 12. 3. Siebert, N., Leopold, J., Zumpe, M., Troschke-Meurer, S., Biskupski, S., Zikoridse, A., and Lode, H.N. (2022). The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD(2) Antibody Dinutuximab Beta. Cancers, 14. 4. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): A multicentre, randomised, phase 3 trial;Ladenstein;Lancet Oncol.,2018 5. Low CD4+/CD25+/CD127− regulatory T cell- and high INF-γ levels are associated with improved survival of neuroblastoma patients treated with long-term infusion of ch14.18/CHO combined with interleukin-2;Siebert;Oncoimmunology,2019
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