Koyama S, Koike N, Adachi S
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-City, Ibaraki, Japan.
J Cancer Res Clin Oncol. 2001 Jan;127(1):20-6. doi: 10.1007/s004320000181.
We investigated the presence and functional status of surface expression of the Fas receptor (FasR) and its ligand (FasL) in tumor and tumor-infiltrating lymphocytes (TIL) in gastric carcinoma (n = 36) from the primary locus, metastatic gastric carcinoma (n = 30) from malignant ascites, and benign gastric mucosa (n = 30) for the control. The quantitative analysis was based on the percentage of positive cells by a flow cytometry. The results showed that the membrane-bound FasL molecule was constitutively expressed in primary and metastatic gastric carcinomas as well as normal gastric epithelium in nearly all the patients. In particular, metastatic carcinoma proved to aberrantly express the FasL molecule. On the other hand, FasR expression ranged from minimal or absent in primary and metastatic gastric carcinomas, suggesting that the carcinoma might be rendered less sensitive toward FasR-induced killing. Apoptotic tumor cells detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) were barely identified in primary and metastatic carcinomas. In the analysis of TIL, the expression of FasR and FasL, and apoptotic TIL could not usually be observed in primary gastric carcinoma. In metastatic carcinoma, however, there was significant overexpression of FasR and FasL in immune TIL associated with a higher frequency of apoptotic cell death detected by TUNEL. The results suggest that metastatic carcinoma expressing FasL, but not FasL+ primary carcinoma, might evade the immune attack by apoptotic depletion of activated TIL through the FasR/FasL systems. These results provide the direct and quantitative evidence of FasR counterattacks and/or paracrine fratricides as a mechanism of tumor-immune escape in vivo in human cancer.
我们研究了原发性胃癌（n = 36）、恶性腹水转移性胃癌（n = 30）以及作为对照的良性胃黏膜（n = 30）中肿瘤及肿瘤浸润淋巴细胞（TIL）表面Fas受体（FasR）及其配体（FasL）的表达情况和功能状态。定量分析基于流式细胞术检测的阳性细胞百分比。结果显示，几乎所有患者的原发性和转移性胃癌以及正常胃上皮中均组成性表达膜结合FasL分子。特别是，转移性癌被证明异常表达FasL分子。另一方面，原发性和转移性胃癌中FasR表达极少或无表达，提示癌组织可能对FasR诱导的杀伤敏感性降低。在原发性和转移性癌中，通过末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记法（TUNEL）检测到的凋亡肿瘤细胞极少。在TIL分析中，原发性胃癌中通常观察不到FasR和FasL的表达以及凋亡TIL。然而，在转移性癌中，免疫TIL中FasR和FasL有显著过表达，同时通过TUNEL检测到凋亡细胞死亡频率更高。结果表明，表达FasL的转移性癌，而非FasL阳性原发性癌，可能通过FasR/FasL系统使活化的TIL凋亡耗竭，从而逃避免疫攻击。这些结果为FasR反击和/或旁分泌自相残杀作为人类癌症体内肿瘤免疫逃逸机制提供了直接和定量的证据。
