Ferrarini M, Imro M A, Sciorati C, Heltai S, Protti M P, Pellicciari C, Rovere P, Manfredi A A, Rugarli C
Laboratorio di Immunologia dei Tumori, Divisione di Medicina II, H San Raffaele Scientific Institute, Milan, Italy.
Int J Cancer. 1999 May 17;81(4):573-9. doi: 10.1002/(sici)1097-0215(19990517)81:4<573::aid-ijc12>3.0.co;2-w.
Fas and Fas ligand (FasL) have been found both in lymphoid and in non-lymphoid malignancies, and are thought to play a role in the interplay between tumors and the immune system. Here we investigated Fas/FasL expression, function and intracellular signalling pathways in human melanomas. Of 5 melanoma cell lines, 3 expressed Fas at their surface, and all of them expressed FasL. FasL was functional, since it triggered Fas-induced apoptosis of human T lymphocytes clones. Conversely, cross-linking of Fas molecule with a specific monoclonal antibody failed to induce apoptosis in any of the melanomas tested, or ceramide intracellular accumulation or caspase-3 activation, pointing to an early alteration in the Fas-triggered signaling cascade. All melanomas retained the ability to undergo apoptosis induced by cytotoxic lymphocytes, which was mediated by the granule exocytosis mechanism. This suggests that melanoma cells evade immune-mediated Fas-triggered apoptosis via a selective blockade of the Fas apoptotic pathway. Cytotoxic lymphocytes, however, may circumvent tumor resistance to Fas-induced death via granzyme-mediated apoptosis, further supporting the development of immunotherapeutic strategies in the treatment of cancer.
Fas和Fas配体（FasL）在淋巴样和非淋巴样恶性肿瘤中均有发现，被认为在肿瘤与免疫系统的相互作用中发挥作用。在此，我们研究了人黑色素瘤中Fas/FasL的表达、功能及细胞内信号传导途径。在5种黑色素瘤细胞系中，3种在其表面表达Fas，且所有细胞系均表达FasL。FasL具有功能，因为它能触发Fas诱导的人T淋巴细胞克隆凋亡。相反，用特异性单克隆抗体交联Fas分子未能在任何测试的黑色素瘤中诱导凋亡，也未诱导神经酰胺在细胞内蓄积或半胱天冬酶-3激活，这表明Fas触发的信号级联反应存在早期改变。所有黑色素瘤均保留了被细胞毒性淋巴细胞诱导凋亡的能力，这是由颗粒胞吐机制介导的。这表明黑色素瘤细胞通过选择性阻断Fas凋亡途径逃避免疫介导的Fas触发的凋亡。然而，细胞毒性淋巴细胞可能通过颗粒酶介导的凋亡规避肿瘤对Fas诱导死亡的抗性，这进一步支持了免疫治疗策略在癌症治疗中的发展。
