Zhang Yi, Luo Feifei, Dong Kuiran
Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai 201102, P.R. China.
Biotherapy Research Center, Fudan University, Shanghai 200040, P.R. China.
Oncol Lett. 2023 May 24;26(1):297. doi: 10.3892/ol.2023.13883. eCollection 2023 Jul.
T cell-based immunotherapy has achieved remarkable beneficial clinical outcomes. Tumor-derived NKG2D ligands (NKG2DL) allow tumors to escape immunologic surveillance. However, the mechanism underlying NKG2DL-mediated immune escape in neuroblastoma (NB) remains incompletely understood. In the present study, first soluble NKG2DL, soluble major histocompatibility complex (MHC) class-I-related chain A and soluble UL-16 binding proteins expression levels were determined in both the serum from patients with NB and in NB cell line culture supernatants. NB cell-derived sNKG2DL was initially cleaved by ADAM10 and ADAM17. Furthermore, sNKG2DL expression levels were positively correlated with the immunosuppressive microenvironment and poor prognosis. Tumor-derived sNKG2DL induced degradation of NKG2D on CD8 T cells and impaired CD8 T cell proliferation, IFN-γ production, and CD107a translocation. More importantly, blockage of sNKG2DL increased the antitumor activity of CD8 T cells. Thus, the results showed that NB-induced immunosuppression was achieved through tumor-derived sMICA and sULBP-2, and blockage of the tumor-derived sNKG2DLs with sNKG2DL neutralizing antibodies was a novel strategy to recover T-cell function and enhance antitumor immunotherapy.
基于T细胞的免疫疗法已取得显著的临床有益效果。肿瘤来源的NKG2D配体（NKG2DL）使肿瘤能够逃避免疫监视。然而，神经母细胞瘤（NB）中NKG2DL介导的免疫逃逸的潜在机制仍未完全了解。在本研究中，首先测定了NB患者血清和NB细胞系培养上清液中可溶性NKG2DL、可溶性主要组织相容性复合体（MHC）I类相关链A和可溶性UL-16结合蛋白的表达水平。NB细胞来源的可溶性NKG2DL最初由ADAM10和ADAM17切割。此外，可溶性NKG2DL表达水平与免疫抑制微环境和不良预后呈正相关。肿瘤来源的可溶性NKG2DL诱导CD8 T细胞上的NKG2D降解，并损害CD8 T细胞增殖、IFN-γ产生和CD107a易位。更重要的是，阻断可溶性NKG2DL可增强CD8 T细胞的抗肿瘤活性。因此，结果表明NB诱导的免疫抑制是通过肿瘤来源的可溶性MICA和可溶性ULBP-2实现的，用可溶性NKG2DL中和抗体阻断肿瘤来源的可溶性NKG2DL是恢复T细胞功能和增强抗肿瘤免疫疗法的一种新策略。
