Abstract
Combined yeast derived β-glucan in conjunction with anti-tumor mAb therapy have demonstrated significant therapeutic efficacy. Therefore, we tested this strategy using human carcinomas implanted in immunocompromised SCID mice. Surprisingly, combined therapy achieved significant therapeutic efficacy in NCI-H23 human non-small cell lung carcinoma but failed in SKOV-3 human ovarian carcinoma. Immunohistochemistry analysis demonstrated markedly decreased levels of neutrophil infiltration and C5a deposition in SKOV-3 tumors compared to that in NCI-H23 tumors. Membrane complement regulatory proteins such as CD46 and CD55 were up-regulated in SKOV-3 cells. Blockade of CD46 and CD55 in vitro led to enhanced deposition of complement C3 activation product C3b on SKOV-3 cells. However, β-glucan-elicited in vitro CR3-dependent cellular cytotoxicity was only augmented in the presence of anti-CD55 mAb. To investigate the role of CD55 in the regulation of β-glucan mediated immunotherapy in vivo, anti-CD55 mAb was co-administered with yeast β-glucan and anti-Her-2/neu mAb to treat previously failed SKOV-3 tumors. Strikingly, significant tumor regression and long term survival were achieved in this model. Blockade of CD55 in vivo also restored neutrophil influx into tumor and C5a deposition. Thus, these studies identify a critical role for CD55 to regulate iC3b and C5a release and in turn to influence the recruitment of β-glucan primed neutrophils eliciting killing activity.
