Differential response of human and mouse dendritic cells to VEGF determines interspecies discrepancies in tumor-mediated TH1/TH2 polarity shift.

PURPOSE: Metastatic cancer patients exhibit systemic dysregulation of immune polarity and are biased toward Th-2 immune responses. This is due, at least in part, to effects of VEGF on antigen presenting cell (APC) function. We therefore compared immune polarity changes in mouse models of cancer with those seen in human patients.

EXPERIMENTAL DESIGN: We measured plasma levels of vascular growth factors and multiple cytokines via ELISA and multiplex analysis in mice with transplantable and spontaneous tumors. We compared immune cell subsets in naive and vaccinated mice with and without tumors. We assessed cytokine immune responses by multiplex analysis. Finally, we assessed gene expression and receptor surface expression in response to VEGF in mouse and human APCs.

RESULTS: Although human patients have elevated plasma cytokines and altered immune polarity in response to antigen, mice have minimal immune abnormalities. Mouse VEGF does not mediate immune repolarization in vitro. Human but not mouse APCs upregulate VEGFR2 and downregulate interleukin (IL)-12β in response to VEGF.

CONCLUSIONS: Whereas humans with metastatic cancer demonstrate dysregulated immune polarity in response to excess plasma VEGF, tumor mice do not. This appears to be due to differences in APC responses to VEGF stimulation. Differential immune effects of VEGF may represent a key species difference in the context of translation of preclinical cancer immunotherapeutics into early clinical testing.