Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment
Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment
复制标题
靶向neuropilin-1消除抗pd -1上调的调节性T细胞，并与4-1BB激动剂协同治疗肝癌
DOI：
10.1097/hep.0000000000000320
复制
发表时间：
2023-02
期刊：
影响因子：
13.5
通讯作者：
Qinchuan Wu;C. Pan;Yuan Zhou;Shuai Wang;Liting Xie;Wu-hua Zhou;Limin Ding;Tianchi Chen;Junjie Qian;Rong Su;Xingxing Gao;Zhibin Mei;Yiting Qiao;Shengyong Yin;Yi Wu;Jieyi Wang;Lin Zhou;Shusen Zheng
中科院分区：
文献类型：
--
作者：
Qinchuan Wu;C. Pan;Yuan Zhou;Shuai Wang;Liting Xie;Wu-hua Zhou;Limin Ding;Tianchi Chen;Junjie Qian;Rong Su;Xingxing Gao;Zhibin Mei;Yiting Qiao;Shengyong Yin;Yi Wu;Jieyi Wang;Lin Zhou;Shusen Zheng
背景与目的：调节性T细胞是PD-1拮抗剂介导的抗肿瘤效应的障碍。然而，肝细胞癌中Tregs对抗PD-1抗体的反应行为以及Tregs组织从外周淋巴组织到肿瘤的适应特征仍不清楚。方法与结果：在这里，我们确定PD-1单一疗法潜在地增加了肿瘤CD4+Tregs的积聚。从机制上讲，抗PD-1抗体介导Tregs在淋巴组织中的增殖而不是在肿瘤中。外周Tregs负荷增加可补充瘤内Tregs，提高瘤内CD4+Tregs与CD8+T细胞的比例。随后，单细胞转录组发现，NRP-1支持Tregs的迁移行为，而CREM和Tnfrsf9基因调节末端抑制性Tregs的行为。NRP-1+4-1BB-Tregs从淋巴组织向肿瘤内逐步发展为NRP-1-4-1BB+Tregs。此外，Treg限制性的Nrp1缺失取消了抗PD-1上调的肿瘤内Tregs负荷，并与4-1BB激动剂协同增强抗肿瘤反应。最后，在人源化的肝癌模型中，NRP-1抑制剂和4-1BB激动剂的联合应用显示了良好和安全的结果，并唤起了PD-1阻断的抗肿瘤作用。结论：我们的研究结果阐明了抗PD-1介导的Tregs在肝癌中积聚的潜在机制，揭示了Tregs的组织适应特性，并确定了靶向NRP-1和4-1BB的治疗潜力，以重新编程肝癌的微环境。
Background & Aims: Regulatory T cells (Tregs) are an obstacle to PD-1 blockade-mediated antitumor efficacy. However, the behaviors of Tregs response to anti-PD-1 in HCC and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues to the tumor are still unclear. Approach & Results: Here, we determine that PD-1 monotherapy potentially augments the accumulation of tumor CD4+ Tregs. Mechanistically, anti-PD-1 mediates Tregs proliferation in lymphoid tissues rather than in the tumor. Increased peripheral Tregs burden replenishes intratumoral Tregs, raising the ratio of intratumoral CD4+ Tregs to CD8+ T cells. Subsequently, single-cell transcriptomics revealed that neuropilin-1 (Nrp-1) supports Tregs migration behavior, and the genes of Crem and Tnfrsf9 regulate the behaviors of the terminal suppressive Tregs. Nrp-1+4-1BB- Tregs stepwise develop to the Nrp-1-4-1BB+ Tregs from lymphoid tissues into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with the 4-1BB agonist to enhance the antitumor response. Finally, a combination of the Nrp-1 inhibitor and the 4-1BB agonist in humanized HCC models showed a favorable and safe outcome and evoked the antitumor effect of the PD-1 blockade. Conclusion: Our findings elucidate the potential mechanism of anti-PD-1–mediated intratumoral Tregs accumulation in HCC and uncover the tissue adaptation characteristics of Tregs and identify the therapeutic potential of targeting Nrp-1 and 4-1BB for reprogramming the HCC microenvironment.