REGULATION OF TUMOR VESSEL FORMATION BY THE IMMUNE SYSTEM

TWEAK及其受体Fn 14分别属于肿瘤坏死因子（TNF）超家族和TNF受体超家族。我们以前已经表明，TWEAK诱导产生促炎趋化因子，细胞迁移，增殖，并通过Fn 14细胞死亡。为了研究TWEAK/Fn 14相互作用在肿瘤相关血管生成和巨噬细胞的肿瘤排斥中的作用，我们产生了抗鼠TWEAK单克隆抗体（mAb）和表达TWEAK或Fn 14的转染子。我们研究了肿瘤细胞中TWEAK或Fn 14表达对体内肿瘤生长的影响。给予中和性抗TWEAK mAb显著降低了肿瘤排斥反应的频率，并缩短了腹腔内接种TWEAK敏感性Fn 14表达肿瘤细胞的小鼠的生存期。此外，抗TWEAK mAb处理促进了TWEAK敏感的Fn 14表达肿瘤细胞的皮下生长，并且这种促进作用通过抑制巨噬细胞浸润而不是NK细胞耗竭而消除。相比之下，即使肿瘤细胞表达Fn 14，给予抗TWEAK mAb对TWEAK耐药肿瘤细胞的生长也没有明显影响。这些结果表明TWEAK介导巨噬细胞的体内抗肿瘤作用。考虑到肿瘤细胞中的TWEAK表达对皮下肿瘤生长没有显著影响，TWEAK/Fn 14相互作用似乎没有通过增强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.