Purpose: Immune checkpoint inhibitors (ICIs) have been developed for clinical application and proven effective for non-small cell lung cancer (NSCLC). Blockade of the programmed cell death 1 (PD-1) protein can partially reinvigorate circulating exhausted-phenotype CD8+ T cells (Tex cells) in preclinical models, however the clinical implication in anti-PD-1-based immunotherapy in NSCLC is unknown.
Methods: Serum specimens were obtained before and during treatment from 145 patients with NSCLC patients who received anti-PD-1 treatment and their prognoses were followed-up. Indicators such as cell subpopulations, T cell invigoration were detected by clinical laboratory testing. Survival curves were estimated by the Kaplan-Meier method, Cox regression analysis was used to identify factors associated with prognoses of NSCLC patients.
Results: The expressions of Ki-67 in PD-1+/CD8+ T cells in most NSCLC patients (97 of 145 cases) increased after treatment. The responding Ki-67+/CD8+ T cell population was mainly CD45RAlo CD27hi, containing cells with high expression of CTLA-4, PD-1, and 2B4 and low expression of NKG2-D (P < 0.0001). The maximum fold change of Ki-67+/PD-1+/CD8+T cells in treatment cycles and the tumor burden determined by imaging may be associated with survival. Patients with higher Ki-67 expression on PD-1+CD8+ T-cells (pretreatment) had statistically significant increased progression-free survival (PFS). A Ki-67 expression to tumor burden ratio greater than 0.6 at the 1st cycle of anti-PD-1 immunotherapy was associated with improvement of PFS and overall survival (P < 0.05).
Conclusion: Activation of circulating Tex cells before or during therapy related to tumor burden may be associated with clinical efficacy of anti-PD-1 immune therapy in NSCLC.

Keywords: non-small cell lung cancer, immunotherapy, T cell invigoration, prognosis


中文翻译：

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T 细胞激活与非小细胞肺癌抗 PD-1 免疫疗法的临床反应相关

目的：免疫检查点抑制剂（ICIs）已开发用于临床应用，并被证明对非小细胞肺癌（NSCLC）有效。在临床前模型中，阻断程序性细胞死亡 1 (PD-1) 蛋白可以部分恢复循环衰竭表型 CD8+ T 细胞 (Tex 细胞)，但其在 NSCLC 中基于抗 PD-1 的免疫治疗的临床意义尚不清楚。
方法：采集145例接受抗PD-1治疗的NSCLC患者治疗前和治疗期间的血清标本，并对其预后进行随访。通过临床实验室检测检测细胞亚群、T细胞活力等指标。采用Kaplan-Meier法估计生存曲线，采用Cox回归分析确定与NSCLC患者预后相关的因素。
结果：大多数NSCLC患者（145例中的97例）治疗后PD-1+/CD8+ T细胞中Ki-67的表达增加。响应的Ki-67+/CD8+ T细胞群主要是CD45RAlo CD27hi，包含高表达CTLA-4、PD-1和2B4和低表达NKG2-D的细胞(P < 0.0001)。治疗周期中Ki-67+/PD-1+/CD8+T细胞的最大倍数变化以及通过成像确定的肿瘤负荷可能与生存相关。PD-1+CD8+ T 细胞上 Ki-67 表达较高的患者（治疗前）的无进展生存期 (PFS) 显着增加，具有统计学意义。在抗 PD-1 免疫治疗的第一个周期，Ki-67 表达与肿瘤负荷比大于 0.6 与 PFS 和总生存期的改善相关（P < 0.05）。
结论：与肿瘤负荷相关的治疗前或治疗期间循环 Tex 细胞的激活可能与 NSCLC 中抗 PD-1 免疫治疗的临床疗效相关。

关键词：非小细胞肺癌，免疫治疗，T细胞激活，预后