Berghoff Anna Sophie, Ricken Gerda, Wilhelm Dorothee, Rajky Orsolya, Widhalm Georg, Dieckmann Karin, Birner Peter, Bartsch Rupert, Preusser Matthias
Department of Medicine I and Comprehensive Cancer Center CNS Unit (CCC-CNS), Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
J Neurooncol. 2016 Oct;130(1):19-29. doi: 10.1007/s11060-016-2216-8. Epub 2016 Jul 19.
Brain metastases (BM) are frequent in small cell lung cancer (SCLC). Novel insights into their pathobiology are needed for development of better therapies. We investigated tumor-infiltrating lymphocyte (TIL) subsets (CD3+, CD8+, CD45RO+, FOXP3+ and PD-1+) and expression of PD-L1 in a series of 32 SCLC BM specimens and four matched primary tumor specimens using immunohistochemistry. 30/32 (93.8 %) BM specimens showed TIL infiltration. CD3+ TILs were observed in 30/32 (93.8 %) BM specimens, CD8+ TILs in 25/32 (78.1 %), CD45RO+ TILs in 15/32 (46.9 %), FOXP3+ TILs in 15/32 (46.9 %) and PD-1+ TILs in 1/32 (3.1 %) BM specimens. Patients with infiltration of CD45RO+ TILS had a significantly longer median survival time (11 months; 95 % CI 0.000-26.148) as compared to patients without the presence of CD45RO+ TILs (5 months; 95 % CI 0.966-9.034; p = 0.007; log rank test). Membranous PD-L1 on tumor cells was observed in 24/32 (75.0 %) BM specimens, with 11/32 (34.4 %) cases showing PD-L1 expression in over 5 % of viable BM tumor cells. PD-L1 expression on TILs was seen in 8/32 (25.0 %) and on tumor infiltrating macrophages in 9/32 (28.1 %) cases. Patients with PD-L1 expression on TILs presented with improved survival prognosis (6 versus 29 months; p = 0.002; log rank test). Among matched primary tumors, all (4/4; 100 %) specimens showed TIL infiltration, while PD-L1 expression found in only 1/4 (25.0 %) specimen. TIL infiltration and PD-L1 expression are commonly found in SCLC BM and presence of CD45RO+ memory T-cells and PD-L1+ TILs in SCLC BM seem to associate with favorable survival times. Our data suggest an active immune microenvironment in SCLC BM that may be targetable by immune-modulating drugs.
脑转移（BM）在小细胞肺癌（SCLC）中很常见。为了开发更好的治疗方法，需要对其病理生物学有新的见解。我们使用免疫组织化学方法，对32例SCLC脑转移标本和4例匹配的原发性肿瘤标本进行研究，分析肿瘤浸润淋巴细胞（TIL）亚群（CD3 +、CD8 +、CD45RO +、FOXP3 +和PD-1 +）以及PD-L1的表达情况。32例BM标本中有30例（93.8%）显示有TIL浸润。32例BM标本中有30例（93.8%）观察到CD3 + TIL，25例（78.1%）观察到CD8 + TIL，15例（46.9%）观察到CD45RO + TIL，15例（46.9%）观察到FOXP3 + TIL，1例（3.1%）观察到PD-1 + TIL。与没有CD45RO + TIL浸润的患者相比，有CD45RO + TIL浸润的患者中位生存时间显著更长（11个月；95%CI 0.000 - 26.148）（5个月；95%CI 0.966 - 9.034；p = 0.007；对数秩检验）。24例（75.0%）BM标本的肿瘤细胞上观察到膜性PD-L1，11例（34.4%）病例显示超过5%的存活BM肿瘤细胞中有PD-L1表达。8例（25.0%）的TIL上观察到PD-L1表达，9例（28.1%）病例的肿瘤浸润巨噬细胞上观察到PD-L1表达。TIL上有PD-L1表达的患者生存预后改善（6个月对29个月；p = 0.002；对数秩检验）。在匹配的原发性肿瘤中，所有4例（全部；100%）标本均显示有TIL浸润，而仅1例（25.0%）标本中发现有PD-L1表达。TIL浸润和PD-L1表达在SCLC脑转移中很常见，SCLC脑转移中CD45RO +记忆T细胞和PD-L1 + TIL的存在似乎与较好的生存时间相关。我们的数据表明SCLC脑转移中存在活跃的免疫微环境，可能是免疫调节药物的靶向目标。
