Prognostic significance of PD-L1 expression and tumor infiltrating lymphocytes in large cell neuroendocrine carcinoma of lung.
Prognostic significance of PD-L1 expression and tumor infiltrating lymphocytes in large cell neuroendocrine carcinoma of lung.
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发表时间：
2018-10
影响因子：
2.2
通讯作者：
Y. Ohtaki;K. Kaira;J. Atsumi;T. Nagashima;O. Kawashima;T. Ibe;M. Kamiyoshihara;Ryoichi Onozato;A. Fujita;Tomohiro Yazawa;M. Sugano;M. Iijima;S. Nakazawa;K. Obayashi;T. Kosaka;T. Yajima;H. Kuwano;K. Shirabe;A. Mogi;K. Shimizu
中科院分区：
文献类型：
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作者：
Y. Ohtaki;K. Kaira;J. Atsumi;T. Nagashima;O. Kawashima;T. Ibe;M. Kamiyoshihara;Ryoichi Onozato;A. Fujita;Tomohiro Yazawa;M. Sugano;M. Iijima;S. Nakazawa;K. Obayashi;T. Kosaka;T. Yajima;H. Kuwano;K. Shirabe;A. Mogi;K. Shimizu
目的：由于大细胞神经内分泌癌（LCNEC）是一种相对罕见的原发性肺癌组织学类型，因此对LCNEC患者的免疫状况知之甚少。我们旨在阐明程序性细胞死亡配体1 （PD-L1）、CD8、CD4和叉头盒蛋白P3 （Foxp3）在LCNEC中的表达及其对预后的影响。方法回顾性分析95例手术切除的LCNEC患者PD-L1、CD8、CD4和Foxp3的表达。任意强度染色超过1%的肿瘤细胞呈PD-L1阳性，淋巴细胞染色超过5%的肿瘤细胞呈CD8、CD4、Foxp3阳性。结果PD-L1阳性表达70例（74%），CD8阳性表达52例（55%），CD4阳性表达76例（80%），Foxp3阳性表达43例（45%）。PD-L1的表达与淋巴渗透阳性显著相关。肿瘤浸润免疫细胞间相互呈正相关。单因素和多因素分析显示，胸膜浸润阳性和Foxp3阴性表达是影响总生存期（OS）的独立不利预后因素。病理分期晚期、胸膜浸润阳性、癌间质CD4阴性表达、Foxp3阴性表达是影响无复发生存（RFS）的独立不利预后因素。结论Foxp3阳性肿瘤浸润淋巴细胞（TILs）是OS和RFS的独立有利预后因素，而CD4阳性TILs是RFS的独立显著不利预后因素。PD-L1的高频率表达可以支持使用抗程序性细胞死亡1抗体治疗LCNEC。
OBJECTIVES Since large cell neuroendocrine carcinoma (LCNEC) is a relatively rare histologic type of primary lung cancer, little is known about the immunological status of patients with LCNEC. We aimed to clarify the expression and prognostic impact of programmed cell death ligand 1 (PD-L1), CD8, CD4, and Forkhead box protein P3 (Foxp3) in LCNEC. METHODS We retrospectively analyzed PD-L1, CD8, CD4, and Foxp3 expressions in 95 surgically resected LCNEC. PD-L1 positive staining was determined in tumors with more than 1% of tumor cells stained to any intensity, and CD8, CD4, and Foxp3 positivity was determined in tumors with more than 5% of lymphocytes stained. RESULTS Positive expression of PD-L1, CD8, CD4, and Foxp3 was observed in 70 (74%), 52 (55%), 76 (80%), and 43 (45%) tumors, respectively. The expression of PD-L1 was significantly correlated with positive lymphatic permeation. Positive correlations were mutually observed among tumor infiltrating immune cells. Univariate and multivariate analyses showed that positive pleural invasion and Foxp3 negative expression were independent unfavorable prognostic factors for overall survival (OS). Advanced pathological stage, positive pleural invasion, CD4 negative expression in cancer stroma, and Foxp3 negative expression were identified as independent unfavorable prognostic factors for recurrence free survival (RFS). CONCLUSIONS Foxp3 positive tumor infiltrating lymphocytes (TILs) were an independent favorable prognostic factor for both OS and RFS, whereas CD4 positive TILs were an independent significant unfavorable prognostic factor for RFS. The high frequency of PD-L1 expression could support the use of anti-programmed cell death 1 antibody in the treatment of LCNEC.