PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24.1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T cell receptor (TCR) sequencing and cytometry by time-of-flight analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti-PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4⁺, but not CD8⁺, TCR diversity significantly increased during therapy, most strikingly in patients who had achieved complete responses. Additionally, patients who responded to therapy had an increased abundance of activated natural killer cells and a newly identified CD3⁻CD68⁺CD4⁺GrB⁺ subset. These studies highlight the roles of recently expanded, clonally diverse CD4⁺ T cells and innate effectors in the efficacy of PD-1 blockade in cHL.

PD-1 阻断剂在经典霍奇金淋巴瘤 (cHL) 中非常有效，其表现出染色体 9p24.1 上CD274 ( PD-L1 ) 和PDC1LG2 ( PD-L2 ) 的频繁拷贝数增加。然而，在这种主要是 MHC-I 类阴性的肿瘤中，抗 PD-1 疗法的作用机制仍未明确。我们通过飞行时间分析利用 T 细胞受体 (TCR) 测序和细胞计数的互补方法，在 CheckMate 205 II 期临床试验 (NCT02181738) 中治疗的 56 名患者中获得对 PD-1 阻断反应的外周免疫特征. 抗 PD-1 疗法对具有多样化基线 TCR 库和治疗期间单克隆相关扩增的患者最有效。CD4 ⁺, 而不是 CD8 ⁺ , TCR 多样性在治疗期间显着增加, 在达到完全反应的患者中最为显着。此外，对治疗有反应的患者激活的自然杀伤细胞和新发现的 CD3 ⁻ CD68 ⁺ CD4 ⁺ GrB ⁺亚群数量增加。这些研究强调了最近扩增的、克隆多样的 CD4 ⁺ T 细胞和先天效应子在 cHL 中 PD-1 阻断功效中的作用。