In my laboratory, we have recently discovered a novel subset of antigen-presenting cells accumulating in human and murine ovarian cancer as well as other tumors, which we named """"""""vascular leukocyte"""""""" (VLCs). VLCs are endowed with vasculogenic potential, but are also bestowed with properties of regulatory antigen- presenting cells. Our data suggest that VLCs play a critical role in expanding Treg in the tumor microenvironment. We hypothesize that this is accomplished through two complementary mechanisms, namely (a) through induction and expansion, and (b) through recruitment of Treg. Our data show that vascular endothelial growth factor (VEGF) induces the generation of VLCs from DC precursors in tumor. Our work also shows for the first time that tumor VEGF paralyzes antitumor effector immune mechanisms. We hypothesize that this is mediated by VLCs through induction of Treg, and that neutralization of VLCs through VEGF blockade will enhance therapies targeting Treg. We will test these hypotheses through three Specific Aims.
Specific Aim -1 will understand how VLCs induce Treg. We will test the hypothesis that VLCs are a novel subtype of regulatory DCs which induce tumor-specific Treg. We will investigate systematically the ability of VLCs to induce CD4+ Treg in vitro and in vivo and examine whether Treg induction is due to expansion of CD4+ CD25+ cells and/or conversion of CD4+ CD25- cells. We will also test whether Treg induction is cell contact- or MHC-II dependent, and tumor antigen-specific. Finally, we will examine whether VEGF blockade attenuates Treg induction by VLCs.
Specific Aim -2 will determine whether VLCs recruit Treg. We will test the hypothesis that VLCs can directly recruit Treg via beta-defensins, and possibly, other chemokines. This is an alternate and complementary pathway by which VLCs may exert their tolerogenic function to expand Treg in tumors. We will test this hypothesis and uncover the link between VEGF and Treg recruitment via chemokines.
Specific Aim -3 will evaluate the effect of VLC neutralization on Treg targeting therapy. We will test the hypothesis that VLCs constitute a tolerogenic ARC platform that generates Treg within the tumor microenvironment. Thus, we hypothesize that VLC neutralization through VEGF blockade will attenuate generation of Treg and will enhance Treg targeting therapy. We will show whether VLCs expand Treg within the tumor. In addition, we will test whether VEGF blockade will decrease the frequency of VLCs and Treg in the tumor; enhance the efficacy of Treg depletion therapy through anti-DC25 antibody; and enable the orchestration of antitumor immune response. ? ? ?
| Facciabene, Andrea; Motz, Gregory T; Coukos, George (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72:2162-71 |
| Facciabene, Andrea; Peng, Xiaohui; Hagemann, Ian S et al. (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475:226-30 |
| Adams, Sarah F; Levine, Douglas A; Cadungog, Mark G et al. (2009) Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer. Cancer 115:2891-902 |
| Christian, Natalie A; Benencia, Fabian; Milone, Michael C et al. (2009) In vivo dendritic cell tracking using fluorescence lifetime imaging and near-infrared-emissive polymersomes. Mol Imaging Biol 11:167-77 |
| Kryczek, Ilona; Wei, Shuang; Zhu, Gefeng et al. (2007) Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 67:8900-5 |
