荷兰玛西玛公主儿科肿瘤中心Judith Wienke等研究人员，通过单细胞RNA测序对神经母细胞瘤进行整合分析，确定NECTIN2-TIGIT轴为免疫疗法靶标。相关论文于2024年1月4日在线发表在《癌细胞》杂志上。

由于新型和改良的免疫疗法可能会满足这一需求，研究人员通过对24个肿瘤（化疗前10个，化疗后14个，包括5对肿瘤）进行单细胞RNA测序，剖析了神经母细胞瘤中的免疫调节相互作用，以确定优化免疫疗法疗效的策略。神经母细胞瘤由自然杀伤细胞（NK）、T细胞、B细胞和免疫抑制性髓细胞群浸润。NK细胞的细胞毒性降低，T细胞功能失调。

相互作用分析揭示了一个庞大的免疫调节网络，并确定NECTIN2-TIGIT是一个关键的免疫检查点。联合阻断TIGIT和PD-L1可显著降低神经母细胞瘤的生长，并在体内产生完全应答（CR）。此外，在化疗耐药的Th-ALK^F1174L/MYCN 129/SvJ合成模型中，将TIGIT+PD-L1阻断加入标准复发治疗可诱导CR。

总之，这些综合分析为免疫治疗联合策略提供了有前景的靶点和理论依据。

据悉，小儿高危神经母细胞瘤患者的生存率很低，迫切需要副作用更小的有效治疗方案。

附：英文原文

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

Author: 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

Issue&Volume: 2024-01-04

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-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.

DOI: 10.1016/j.ccell.2023.12.008

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00436-1