美国乔治城大学Samir N. Khleif团队发现在亚活化CD8细胞中的PD-1阻断会导致抗PD-1疗法的抗性。相关论文于2019年9月发表在《自然—免疫学》杂志上。

了解对程序性细胞死亡蛋白1（PD-1）抗体（anti-PD-1）的抗性，对与逆转治疗策略的发展至关重要。

研究人员发现，在抗PD-1抗性模型中，同时进行抗PD-1和疫苗疗法能够逆转抗性，而在抗原活化前阻断PD-1会消除治疗效果。这是由于在由肿瘤诱导引发的非最佳CD8细胞活化条件下，通过PD-1阻断诱导出功能失调的PD-1阳性、CD38高表达、CD8阳性细胞。这导致错误的T细胞受体信号传导和对抗原再刺激的无应答。另一方面，最佳活化CD8细胞的PD-1阻断阻止了功能失调的CD8细胞的产生，从而逆转了抗性。消耗PD-1阳性、CD38高表达、CD8阳性细胞增强了治疗效果。

此外，无应答的患者在肿瘤和血液中观察到出比应答者更多的PD-1阳性、CD38高表达、CD8阳性细胞。总之，CD8 阳性T细胞活化的状态是抗PD-1治疗抗性的主要贡献者。未活化或非最优活化的CD8细胞中的PD-1阻断通过诱导PD-1阳性、CD38高表达、CD8阳性细胞产生抗性，而通过最佳活化可以逆转抗性。PD-1阳性、CD38高表达、CD8阳性细胞可以作为抗PD-1治疗的预测和治疗生物标志物。抗PD-1和疫苗的测序对于成功治疗至关重要。

附：英文原文

Title: PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1 + CD38 hi cells and anti-PD-1 resistance

Author: Vivek Verma, Rajeev K Shrimali, Shamim Ahmad, Winjie Dai, Hua Wang, Sumin Lu, Rahul Nandre, Pankaj Gaur, Jose Lopez, Moshe Sade-Feldman, Keren Yizhak, Stacey L. Bjorgaard, Keith T. Flaherty, Jennifer A. Wargo, Genevieve M. Boland, Ryan J. Sullivan, Gad Getz, Scott A. Hammond, Ming Tan, Jingjing Qi, Phillip Wong, Taha Merghoub, Jedd Wolchok, Nir Hacohen, John E. Janik, Mikayel Mkrtichyan, Seema Gupta, Samir N. Khleif

Issue&Volume: Volume 20 Issue 9

Abstract: Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.

DOI: 10.1038/s41590-019-0441-y

Source:https://www.nature.com/articles/s41590-019-0441-y