REGULATION OF TUMOR VESSEL FORMATION BY THE IMMUNE SYSTEM

TWEK及其受体Fn14分别属于肿瘤坏死因子超家族和肿瘤坏死因子受体超家族。我们之前已经证明，TWEEP通过Fn14诱导促炎趋化因子的产生，细胞迁移、增殖和细胞死亡。为了研究TWEEP/Fn14相互作用在肿瘤相关血管生成和巨噬细胞的肿瘤排斥反应中的作用，我们制备了抗TWEK的单抗，并表达了TWEK或Fn14的转基因细胞。我们检测了TWEE或Fn14在肿瘤细胞中的表达对体内肿瘤生长的影响。给予中和抗TWAKN14单抗可显著减少肿瘤排斥反应的发生，并缩短小鼠的生存期。此外，抗TWAKE单抗治疗可促进TWEWE敏感的Fn14表达肿瘤细胞的皮下生长，这种促进作用可被巨噬细胞侵袭的抑制而不是NK细胞的耗竭所抵消。相反，即使肿瘤细胞表达Fn14，给予抗TWEAM单抗对TWEY耐药肿瘤细胞的生长也没有明显的影响。这些结果表明，TWEKE在体内介导了巨噬细胞的抗肿瘤作用。认为TWEK在肿瘤细胞中的表达对皮下肿瘤生长无明显影响，TWEW/Fn14相互作用似乎没有通过促进血管生成来促进肿瘤生长。

TWEAK and its receptor, Fn14 belong to the tumor necrosis factor (TNF) superfamily and the TNF receptor superfamily, respectively. We have previously shown that TWEAK induces production of pro-inflammatory chemokine, cell migration, proliferation, and cell death through Fn14. To investigate roles for TWEAK/Fn14 interaction in tumor-associated angiogenesis and tumor rejection by macrophages, we generated anti-murine TWEAK monoclonal antibody (mAb), and transfectants expressing TWEAK or Fn14. We examined the effect of TWEAK or Fn14 expression in tumor cells on tumor outgrowth in vivo. Administration of neutralizing anti-TWEAK mAb significantly reduced the frequency of tumor rejection and shortened the survival of mice intraperitoneally inoculated with TWEAK-sensitive Fn14-expressing tumor cells. Moreover, anti-TWEAK mAb treatment promoted the subcutaneous growth of TWEAK-sensitive Fn14-expressing tumor cells, and this promotion was abolished by the inhibition of macrophage infiltration but not NK cell depletion. In contrast, administration of anti-TWEAK mAb had no apparent effect on the growth of TWEAK-resistant tumor cells, even if tumor cells expressed Fn14. These results indicate that TWEAK mediates anti-tumor effect of macrophages in vivo. Taken that TWEAK expression in tumor cells had no significant effect on subcutaneous tumor growth, TWEAK/Fn14 interaction does not appear to promote tumor growth through enhancing angiogenesis.