[摘 要] 目的：探讨嗜酸性粒细胞（Eos）和其他循环血细胞和炎症指标在预测小细胞肺癌（SCLC）免疫治疗疗效和免疫相关 不良反应（irAE）中的价值。方法:回顾分析 2013 年 8 月至 2023 年 7 月期间海军军医大学第一附属医院呼吸科收治的 410 例 SCLC患者临床信息；在化疗或免疫治疗前，以及治疗后的3个周期，分别检测患者全血细胞计数和细胞因子等指标；记录irAE的 发生时间、类型、分级，以及随访情况。结果: 接受化疗联合免疫检查点抑制剂（ICI）治疗（简称联合治疗）的患者116例，其中一 线联合治疗患者91例、后线联合治疗25例。联合组患者的总有效率（ORR）为44.8%，疾病控制率（DCR）为90.5%，单用化疗（单 化）组患者的ORR为38.4%，DCR为85.0%。联合组中位PFS为8.9（7.2～10.5）个月，中位OS为17.7（13.9～21.5）个月。将联合组 与单化组行倾向得分匹配（PSM）法配对，对比二组治疗后3周期的绝对嗜酸性粒细胞计数（AEC）水平、相对嗜酸性粒细胞计数 （REC）水平；计算历次复查Eos水平与基线Eos水平的比值（AECT1/0、AECT2/0、AECT3/0、RECT1/0、RECT2/0、RECT3/0 ），联合组的AECT3/0 和RECT3/0显著高于单化组。单因素分析表明，基线AEC和REC的升高与较好的治疗至失败时间（TTF）和OS显著相关（P < 0.05）； 治疗后Eos水平与基线水平的比例（AECT3/0、RECT3/0 ）与较好的PFS和TTF显著相关（P < 0.05）；RECT3/0升高同样与OS改善显著相 关（P < 0.05）。多因素分析提示，AECT3/0 > 0.41与较好的PFS和TTF显著相关（P < 0.05）；当RECT3/0 > 0.32时，与较好的PFS、TTF、 OS均显著相关（P < 0.05）；RECT3/0 > 0.27仅与较好的TTF、OS显著相关（P < 0.05）。亚组分析发现，缓解组的RECT3/0显著高于非 缓解组（P < 0.05）。一线应用ICI与二线/后线应用ICI患者的PFS、TTF、OS无统计学差异，但一线应用ICI时ORR（50% vs 25%， P < 0.05）和DCR（93.48% vs 79.17%，P < 0.05）显著优于二线/后线。116例联合治疗患者发生43例irAE（35.34%）, 最常见的为免 疫相关性皮炎 8.62%；Ⅲ级以上的 irAE 共 17 例（14.66%）；因 irAE 停药 10 例（8.62%），死亡 2 例;发生 irAE 的患者 PFS 较未发生 irAE的患者显著延长（P < 0.05），而TTF和OS无统计学差异。发生irAE患者的RECT3较未发生irAE患者显著升高（P < 0.05）， AECT3/0 > 0.29 的患者 irAE 发生率显著增高（P < 0.05）。结论: Eos 是 SCLC 接受 ICI 治疗的保护性因素，通过监测 AECT3/0、 RECT3/0，并结合患者的临床病理生理特征、细胞因子和炎症标志物水平进行综合评估，可有效预测SCLC患者的免疫治疗疗效和 irAE的发生。

[Abstract] Objective: To investigate the predictive value of eosinophils (Eos), other circulating blood cells, and inflammatory markers for the efficacy of immunotherapy and immune-related adverse events (irAEs) in small cell lung cancer (SCLC). Methods: A retrospective analysis was conducted on the clinical information of 410 SCLC patients admitted to the Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Second Military Medical University between August 2013 and July 2023. Complete blood cell counts and cytokine levels were measured before chemotherapy/immunotherapy and after three treatment cycles. The onset time, type, grade, and follow-up information of irAEs were recorded. Results: Among the patients, 116 received chemotherapy combined with immune checkpoint inhibitors (ICIs), including 91 with first-line treatment and 25 with later-line treatment. The overall response rate (ORR) was 44.8% and the disease control rate (DCR) was 90.5% in the combination group, compared to 38.4% and 85.0%, respectively, in the chemotherapy-alone group. The median progression-free survival (PFS) was 8.9 (7.2-10.5) months and median overall survival (OS) was 17.7 (13.9-21.5) months in the combination group. After propensity score matching (PSM) between the combination and chemotherapy-alone groups, the levels of absolute eosinophil count (AEC) and relative eosinophil count (REC) after three treatment cycles were compared. Ratios of follow-up Eos levels to baseline levels (AECT1/0, AECT2/0, AECT3/0, RECT1/0, RECT2/0, RECT3/0) were calculated, and the results showed that AECT3/0 and RECT3/0 in the combination group were significantly higher than those in the chemotherapy-alone group. Univariate analysis showed that elevated baseline AEC and REC were significantly associated with better time to treatment failure (TTF) and OS (P < 0.05). The ratio of post-treatment to baseline Eos levels (AECT3/0, RECT3/0) was significantly associated with better PFS and TTF (P < 0.05). Elevated RECT3/0 was also significantly associated with improved OS (P < 0.05). Multivariate analysis indicated that AECT3/0 > 0.41 was significantly associated with better PFS and TTF (P < 0.05), RECT3/0 > 0.32 was significantly associated with better PFS, TTF, and OS (P < 0.05), while RECT3/0 > 0.27 was only significantly associated with better TTF and OS (P < 0.05). Subgroup analysis revealed that RECT3/0 was significantly higher in the response group than in the non-response group (P < 0.05). There was no statistical difference in PFS, TTF, or OS between patients receiving first-line versus second-/later-line ICI therapy. However, ORR (50% vs 25%, P < 0.05) and DCR (93.48% vs 79.17%, P < 0.05) were significantly superior with first-line ICI use. Among the 116 patients in the combination group, 43 (35.34%) experienced irAEs, most commonly immune-related dermatitis (8.62%). Grade Ⅲ or higher irAEs occurred in 17 patients (14.66%), leading to treatment discontinuation in 10 cases (8.62%) and deaths in 2 cases. Patients who experienced irAEs had significantly longer PFS compared to those without irAEs (P < 0.05), while TTF and OS were not significantly different. RECT3 levels were significantly higher in patients with irAEs than in those without (P < 0.05), and AECT3/0 > 0.29 was associated with a significantly higher incidence of irAEs (P < 0.05). Conclusion: Eosinophils represent a protective factor in SCLC patients receiving ICI therapy. Monitoring AECT3/0 and RECT3/0, combined with patient clinicopathological characteristics, cytokines, and inflammatory markers, can effectively predict immunotherapy efficacy and the occurrence of irAEs in SCLC patients.

[基金项目] 上海市卫健委协同创新集群项目资助（2020CXJQ03）；上海市申康重大疾病多中心临床研究项目 （SHDC2020CR1021B-005）