N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells.
N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells.
复制标题
N-钙粘蛋白抑制剂创造一个保护 TIL 免受免疫检查点和 Treg 细胞侵害的微环境
DOI：
10.1136/jitc-2020-002138
复制
发表时间：
2021-03
影响因子：
10.9
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Sun Y;Jing J;Xu H;Xu L;Hu H;Tang C;Liu S;Wei Q;Duan R;Guo J;Yang L
背景很少有前列腺癌患者从目前的免疫治疗中获益。因此，我们的目标是探索改变这种范式的新策略。方法采用人体组织、细胞系和体内实验，研究N-钙粘蛋白是否影响程序性死亡配体1（PD-L1）和吲哚胺2，3-双加氧酶1（IDO-1）的产生，以及N-钙粘蛋白是否促进效应性Treg细胞的产生。然后，我们使用携带PC 3的人源化非肥胖糖尿病/严重联合免疫缺陷IL 2 R γnull（hNSG）小鼠，通过尾静脉注射人CD 34+造血干细胞来评估N-钙粘蛋白拮抗剂N-Ac-CHAVC-NH 2（指定为ADH-1）是否可以改善肿瘤浸润淋巴细胞（TIL）相关治疗的治疗效果。结果N-cadherin通过IFN-γ（interferon-gamma）信号转导和增加游离脂肪酸的产生，显著上调PD-L1和IDO-1的表达，促进eTreg细胞的生成。在临床前实验中，由TIL介导的免疫重建减缓了肿瘤生长并延长了生存时间;然而，在PD-L1、IDO-1和eTreg细胞的免疫系统抑制后，这种作用消失。此外，ADH-1有效地减少免疫抑制和增强TIL相关治疗。结论N-cadherin拮抗剂ADH-1可促进TIL的抗肿瘤效应。肿瘤必须克服这一重要障碍才能对免疫疗法产生反应。
Background Few patients with prostate cancer benefit from current immunotherapies. Therefore, we aimed to explore new strategies to change this paradigm. Methods Human tissues, cell lines and in vivo experiments were used to determine whether and how N-cadherin impacts the production of programmed death ligand-1 (PD-L1) and indole amine 2,3-dioxygenase (IDO-1) and whether N-cadherin can increase the production of effector (e)Treg cells. Then, we used PC3-bearing humanized non-obese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice with an intravenous injection of human CD34+ hematopoietic stem cells into the tail vein to evaluate whether the N-cadherin antagonist N-Ac-CHAVC-NH2 (designated ADH-1) could improve the therapeutic effect of tumor-infiltrating lymphocyte (TIL)-related treatment. Results N-cadherin dramatically upregulated the expression of PD-L1 and IDO-1 through IFN-γ (interferongamma) signaling and increasing the production of free fatty acids that could promote the generation of eTreg cells. In preclinical experiments, immune reconstitution mediated by TILs slowed tumor growth and extended the survival time; however, this effect disappeared after immune system suppression by PD-L1, IDO-1 and eTreg cells. Furthermore, ADH-1 effectively reduced immunosuppression and enhanced TIL-related therapy. Conclusions These data show that the N-cadherin antagonist ADH-1 promotes TIL antitumor responses. This important hurdle must be overcome for tumors to respond to immunotherapy.
登录
查看更多内容
PD-1和PD-L1抑制剂作为癌症免疫疗法的一种形式的开发：对注册试验和未来考虑的全面综述。
影响因子：
10.9
作者：
Gong J;Chehrazi-Raffle A;Reddi S;Salgia R
通讯作者：
Salgia R
影响因子：
17.1
作者：
Amarnath S;Mangus CW;Wang JC;Wei F;He A;Kapoor V;Foley JE;Massey PR;Felizardo TC;Riley JL;Levine BL;June CH;Medin JA;Fowler DH
通讯作者：
Fowler DH
影响因子：
6.2
作者：
Beasley GM;McMahon N;Sanders G;Augustine CK;Selim MA;Peterson B;Norris R;Peters WP;Ross MI;Tyler DS
通讯作者：
Tyler DS
影响因子：
11.2
作者：
Dunn, GP;Sheehan, KCF;Schreiber, RD
通讯作者：
Schreiber, RD
影响因子：
11.2
作者：
Akalay, Intissar;Janji, Bassam;Chouaib, Salem
通讯作者：
Chouaib, Salem