针对神经丛1 (neuropilin-1) 抑制抗-PD-1 上调的调节性 T 细胞，与 4-1BB 激动剂协同治疗肝癌。
Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment.
发表日期：2023 Feb 23
作者：
Qinchuan Wu, Caixu Pan, Yuan Zhou, Shuai Wang, Liting Xie, Wuhua 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
来源：
HEPATOLOGY
摘要：
调节性T细胞（Tregs）是PD-1阻断介导的抗肿瘤疗效的障碍。然而，在肝细胞癌（HCC）中，Tregs对抗PD-1的反应行为及其从外周淋巴组织（LTs）适应肿瘤的特征仍不明确。在此，我们确定了PD-1单药可能增加肿瘤CD4+ Tregs的积累。机制上，抗PD-1介导的Tregs增殖主要发生在LTs而非肿瘤内。外周Tregs的增加使肿瘤内Tregs的比例升高，从而增加了肿瘤内CD4+ Tregs与CD8+ T细胞的比值。随后的单细胞转录组学显示，神经肽1（Nrp-1）支持Tregs的迁移行为，Crem和Tnfrsf9等基因则调节末端抑制Tregs的行为。Nrp-1+4-1BB- Tregs逐步从LTs进入肿瘤转变为Nrp-1-4-1BB+ Tregs。此外，Treg限制性的Nrp1消耗可以消除抗PD-1诱导的肿瘤内Tregs负荷，并与4-1BB激动剂协同增强抗肿瘤反应。最后，在人源性HCC模型中，Nrp-1抑制剂和4-1BB激动剂的联合应用表现出良好和安全的结果，并激发PD-1阻断的抗肿瘤效应。本研究阐明了抗PD-1介导的肝细胞癌肿瘤内Tregs积累的潜在机制，揭示了Tregs的组织适应特性，并确定了靶向Nrp-1和4-1BB重编程肝细胞癌微环境的治疗潜力。版权所有©2023美国肝病研究协会。
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 hepatocellular carcinoma (HCC) and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues (LTs) 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 mediated Tregs proliferation in LTs 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 LTs into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with 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 evoke the antitumor effect of 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.Copyright © 2023 American Association for the Study of Liver Diseases.