PO.IM01.11 · 免疫学
抗PD-1疗效与由具有淋巴结归巢能力的慢性效应细胞组成的克隆轨迹相关
Anti-PD-1 efficacy is associated with a clonal trajectory composed of chronic effectors with lymph node homing capacity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：免疫检查点阻断（ICB），如抗CTLA-4或抗PD-1（alphaPD-1），驱动着不同模式的T细胞分化，最终影响治疗疗效。然而，在人类中识别和定义不同的T细胞分化状态一直具有挑战性。我们应用一种新算法Clonotrace（Nancy Zhang，宾夕法尼亚大学），通过监测alphaPD-1治疗后单个克隆跨分化状态的变化来定义分化轨迹。我们检验以下假设：某些分化轨迹将具有独特的性质，包括细胞状态和迁移模式，这些性质将影响临床疗效。
方法：我们对来自36例接受新辅助alphaPD-1治疗的III期黑色素瘤患者的132,898个CD8+ T细胞进行了单细胞RNA和配对TCR测序，其中12例患者具有匹配的肿瘤、未受累区域淋巴结和血液样本。我们应用Clonotrace，通过将在CD8细胞状态中具有相似转录足迹的克隆型分组来定义分化轨迹。然后，我们从细胞状态组成、抗原特异性、组织分布、基因调控以及与临床结局的关联方面定义了这些分化轨迹。
结果：我们鉴定出10条不同的克隆轨迹，它们从初始/干细胞样CD8 T细胞状态分化为耗竭型和/或效应型CD8 T细胞状态。这些轨迹在很大程度上根据抗原特异性以及与慢性刺激相关的通路表达分为两组克隆。对抗原特异性克隆的进一步检查鉴定出一条特定轨迹（Traj 5），它与临床反应相关。Traj 5包括具有独特慢性效应细胞状态的克隆，这些细胞能够在淋巴结和肿瘤之间迁移。相比之下，Traj 1由终末耗竭的CD8克隆组成，这些克隆驻留于肿瘤中并与alphaPD-1耐药相关。
结论：我们在患者中鉴定出一条独特的分化轨迹，它在慢性刺激环境下保留了效应T细胞分化。这些慢性效应细胞保留了在淋巴结和肿瘤之间迁移的能力，并与alphaPD-1的疗效相关。这些发现表明维持迁移能力对ICB的疗效至关重要。相比之下，终末分化导致CD8 T细胞被"锁定"在组织中并终末耗竭。
查看英文原文 English abstract
Introduction: Immune checkpoint blockade (ICB), such as anti-CTLA-4 or anti-PD-1 (alphaPD-1), drives distinct patterns of T cell differentiation that ultimately influence treatment efficacy. However, it has been challenging to identify and define distinct T cell differentiation states in humans. We apply a novel algorithm Clonotrace (Nancy Zhang, UPenn) to define differentiation trajectories by monitoring single clones across differentiation states after alphaPD-1. We test the hypothesis that certain differentiation trajectories will have unique properties, including cell states and trafficking patterns, that will influence clinical efficacy.
Methods: We performed single cell RNA and paired TCR sequencing on 132,898 CD8+ T cells from 36 stage III melanoma patients treated with neoadjuvant alphaPD-1, including 12 patients with matched tumor, uninvolved regional lymph node, and blood samples. We applied Clonotrace to define differentiation trajectories by grouping clonotypes that have a similar transcriptional footprint across CD8 cell states. We then defined these differentiation trajectories in terms of cell state composition, antigen specificity, tissue distribution, gene regulation, and association with clinical outcomes.
Results: We identified 10 distinct clonal trajectories that differentiate from naïve/stem-like CD8 T cell states to exhausted and/or effector CD8 T cell states. These trajectories largely separated into two sets of clones based on antigen specificity and the expression of pathways associated with chronic stimulation. Further examination of the antigen-specific clones identified one particular trajectory (Traj 5), that was associated with clinical response. Traj 5 included clones with a unique chronic effector cell state that was able to traffic between lymph node and tumor. In contrast, Traj 1 was composed of terminally exhausted CD8 clones that were tumor-resident and associated with alphaPD-1 resistance.
Conclusion: We identify a unique differentiation trajectory in patients that retains effector T cell differentiation in the setting of chronic stimulation. These chronic effectors retain the ability to traffic between lymph node and tumor and are associated with the efficacy of alphaPD-1. These findings indicate maintaining trafficking ability is essential for the efficacy of ICB. In contrast, terminal differentiation results in CD8 T cells becoming “locked” in the tissue and terminally exhausted.
利益披露 Disclosure
M. Wang*, None..
G. Wang*, None..
K. Patel, None..
A. Nandi, None..
T. Lai, None..
S. Rosenberg, None..
Z. Xiang, None..
S. Park, None..
T. C. Mitchell, None..
A. C. Huang#, None.