Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
BMC Cancer. 2021 Jan 5;21(1):19. doi: 10.1186/s12885-020-07727-y.
BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.
背景：免疫检查点阻断（ICBs）在多种晚期实体瘤患者中表现出持久的临床反应和更好的耐受性。然而，我们经常会遇到表现出矛盾性肿瘤快速生长且临床结局较差的超进展性疾病（HPD）患者。本研究旨在探讨临床因素和免疫细胞组成对接受免疫治疗的非小细胞肺癌（NSCLC）患者不同肿瘤反应的影响。
方法：本研究评估了 2014 年 1 月至 2018 年 5 月期间接受 ICB 治疗的 231 例 NSCLC 患者。HPD 定义为 ICB 治疗期间肿瘤生长动力学比>2 倍和治疗失败时间≤2 个月。我们使用多重免疫组化分析了临床数据、影像学研究、周期性血清学指标和肿瘤及基质中的免疫细胞组成。
结果：在 231 例 NSCLC 患者中，50 例（21.6%）和 79 例（34.2%）患者观察到 PR/CR 和 SD，26 例（11.3%）患者符合 HPD 标准。不良反应组（HPD 和非 HPD PD）的中位总生存期明显短于疾病控制组（SD 和 PR/CR）（5.5 和 6.1 个月比 16.2 和 18.3 个月，P=0.000）。多变量分析显示，HPD 与重度吸烟者（p=0.0072）、PD-L1 表达≤1%（p=0.0355）和转移部位≥3 个（p=0.0297）显著相关。在包括 NLR、PLR、CAR 和 LDH 在内的血清学指标中，只有 CAR 在治疗前和免疫治疗开始时以及第 1 次肿瘤评估时与 HPD 始终有显著相关性。CD4+效应 T 细胞和 CD8+细胞毒性 T 细胞以及 CD8+/PD-1+肿瘤浸润淋巴细胞（TIL）的数量趋于减少，尤其是在 HPD 组的基质中。在 HPD 组中，基质中表达 CD14、CD68 和 CD163 的 M2 型巨噬细胞较多，而肿瘤内区域的 CD56+NK 细胞较少。
结论：本研究表明，不仅包括重度吸烟、PD-L1 表达极低、多处转移和 CAR 指数在内的临床因素，而且肿瘤微环境中 CD8+/PD-1+TIL 较少和 M2 巨噬细胞较多，与接受免疫治疗的晚期/转移性 NSCLC 患者发生 HPD 显著相关。
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