Chopin Dominique, Barei-Moniri Reza, Maillé Pascale, Le Frère-Belda Marie-Aude, Muscatelli-Groux Béatrice, Merendino Nicolò, Lecerf Laure, Stoppacciaro Antonella, Velotti Francesca
Service d'Urologie et Groupe d'Etude des Tumeurs Urologiques Equipe Mixte INSERM 03-37, Centre Hôspitalier Universitaire Henri Mondor, Créteil, France.
Am J Pathol. 2003 Apr;162(4):1139-49. doi: 10.1016/S0002-9440(10)63910-7.
The interaction between FasL on tumor cells and Fas on lymphocytes may represent a tumor immune escape mechanism. We explored FasL expression and function in human urinary bladder transitional cell carcinomas (TCCs). FasL expression was observed in situ in 45% of TCCs (n = 45) and was absent in normal urothelium (n = 20). A correlation existed between FasL expression and high tumor grade (0% in G1, 14% in G2, and 75% in G3; P < 0.0001) and stage (13% in superficial Ta-T1 versus 81% in invasive T2-T4; P < 0.0001). FasL function was shown by the ability of two FasL-positive primary culture TCC cell lines (established from two FasL-positive invasive TCCs) to induce Fas-mediated killing not only of conventional Fas-sensitive targets (such as Jurkat cells or phytohemagglutinin-lymphoblasts), but also of autologous T lymphocytes generated in a mixed lymphocyte tumor-cell culture. In addition, an association between FasL expression by TCC cells and activated caspase-8, -9, and -3 expression by interferon-gamma-producing CD8-positive tumor-infiltrating lymphocytes was observed in situ. Our results show a functional expression of TCC-expressed FasL that correlates with tumor progression. These results suggest that TCC-expressed FasL may induce apoptosis of anti-tumor T lymphocytes in vivo, providing new insights on the mechanisms involved in bladder TCC progression.
肿瘤细胞上的FasL与淋巴细胞上的Fas之间的相互作用可能代表一种肿瘤免疫逃逸机制。我们探讨了FasL在人膀胱移行细胞癌（TCC）中的表达及功能。在45%的TCC（n = 45）中观察到FasL原位表达，而在正常尿路上皮（n = 20）中未观察到。FasL表达与高肿瘤分级（G1中为0%，G2中为14%，G3中为75%；P < 0.0001）和分期（浅表Ta-T1期为13%，浸润性T2-T4期为81%；P < 0.0001）相关。两个FasL阳性的原代培养TCC细胞系（由两个FasL阳性的浸润性TCC建立）不仅能够诱导Fas介导的对传统Fas敏感靶细胞（如Jurkat细胞或植物血凝素淋巴细胞）的杀伤，还能诱导在混合淋巴细胞肿瘤细胞培养中产生的自体T淋巴细胞的杀伤，这表明了FasL的功能。此外，原位观察到TCC细胞FasL表达与产生干扰素-γ的CD8阳性肿瘤浸润淋巴细胞中活化的caspase-8、-9和-3表达之间存在关联。我们的结果显示TCC表达的FasL具有与肿瘤进展相关的功能性表达。这些结果表明TCC表达的FasL可能在体内诱导抗肿瘤T淋巴细胞凋亡，为膀胱TCC进展所涉及的机制提供了新的见解。
