Cancer vaccines: Uses of HLA transgenic mice compared to genetically modified mice
ABSTRACT Many tumor antigens have been identified that can be targeted by the immune system. Animal models that have been genetically modified to express human HLA molecules instead of their own MHC antigens have shown to be valuable in the discovery of peptides derived from tumor antigens many of which have since been used in clinical trials with varying degrees of success. Although these models are not perfect, they nonetheless allow transplantable tumor models to be developed to evaluate novel vaccination strategies that can then be applied in humans. In addition animals that have been genetically modified to "spontaneously" generate tumors that will grow within their correct environment are of greater value for studying angiogenesis, metastasis and the relationship between the immune system and tumor in a physiological setting. In this review, mice genetically modified to express HLA genes or to spontaneously develop tumors are discussed, highlighting their advantages and limitations as preclinical models for cancer immunotherapy.
- [Show abstract] [Hide abstract]
ABSTRACT: 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. 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. 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. 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.Clinical Cancer Research 02/2011; 17(7):1776-83. DOI:10.1158/1078-0432.CCR-10-2836 · 8.19 Impact Factor