Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women, accounting for approximately 15,000 deaths in the United States yearly. The overall 5-year survival of ovarian carcinoma is less than 30%, creating a pressing need to understand its biology. This proposal is based on novel evidence from our laboratory, which suggests that transendothelial trafficking and intratumoral accumulation of lymphocytes is associated with dramatically improved clinical outcome in ovarian cancer. Our work shows that endothelial barrier mechanisms are present in poor prognosis tumors lacking intratumoral T cells, while chemo tactic mechanisms are activated in good prognosis tumors, which are successfully infiltrated by T cells. Therefore, this proposal seeks to understand the endothelial pathways preventing intratumoral T cell accumulation and elucidate how such pathways are circumvented by immune mechanisms allowing for the orchestration of an efficient T cell antitumor attack. We postulate that in poor prognosis tumors, under the influence of pro-angiogenic/anti-inflammatory paracrine factors, including vascular endothelial growth factor (VEGF), microvascular endothelium up regulates Fas ligand (FasL), inducing apoptosis and limiting the extravasations of adhering T cells. We further hypothesize that, in good prognosis tumors, this endothelial barrier mechanism is neutralized by interferon-gamma (IFN-gamma)- inducible chemokines, which, in their role of pro-inflammatory/anti-angiogenic factors, deliver potent signals to the endothelium, suppressing FasL and allowing for the survival, extravasations and intratumoral accumulation of T cells. We are proposing to test the above hypotheses through the following Specific Aims:
Specific Aim 1 : To determine the role of FasL in the endothelial barrier to T cell homing, and investigate its paracrine regulation by VEGF and estrogens. We will show how tumor microvascular endothelium controls T cell trafficking and prevents extravasations of effectors T cells through induction of apoptosis. We will test the role of FasL in mediating the endothelial barrier to T cell extravasations in ovarian carcinoma and its regulation by VEGF and estrogen via nitric oxide (NO) in human tumor endothelium.
Specific Aim -2: To assess the role of IFN-gamma-inducible chemokines in suppressing endothelial FasL. We will show how IFN-gamma-inducible chemokines, acting through CXCR3, counteract VEGF and estrogens, suppressing NO production and inhibiting the expression of FasL in human tumor microvascular endothelial cells in vitro.
Specific Aim 3. To test the effect of disrupting the endothelial NO --) FasL pathway on T cell homing in vivo. Using a syngeneic ovarian cancer mouse model that we generated, we will (i) determine how suppression of Fas-FasL interactions at the endothelium can enhance T cell homing in ovarian carcinoma, and (ii) investigate how targeting of VEGF and IFN-gamma-inducible chemokines disrupts NO and FasL in tumor endothelium in the mouse. This work will elucidate novel and fundamental pathways of lymphocyte-endothelial co-operation, which regulate tumor immune attack and critically affect the outcome of ovarian carcinoma. Results obtained from the proposed studies will generate novel ideas for the development of molecular tools to circumvent impediments to tumor immunotherapy.
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| Kandalaft, Lana E; Motz, Gregory T; Busch, Johanna et al. (2011) Angiogenesis and the tumor vasculature as antitumor immune modulators: the role of vascular endothelial growth factor and endothelin. Curr Top Microbiol Immunol 344:129-48 |
| Kandalaft, Lana E; Singh, Nathan; Liao, John B et al. (2010) The emergence of immunomodulation: combinatorial immunochemotherapy opportunities for the next decade. Gynecol Oncol 116:222-33 |
| Kandalaft, Lana E; Facciabene, Andrea; Buckanovich, Ron J et al. (2009) Endothelin B receptor, a new target in cancer immune therapy. Clin Cancer Res 15:4521-8 |
| Buckanovich, Ronald J; Facciabene, Andrea; Kim, Sarah et al. (2008) Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14:28-36 |
| Benencia, Fabian; Coukos, George (2008) Biological therapy with oncolytic herpesvirus. Adv Exp Med Biol 622:221-33 |
| Chase, Dana M; Monk, Bradley J; Wenzel, Lari B et al. (2008) Supportive care for women with gynecologic cancers. Expert Rev Anticancer Ther 8:227-41 |
| Buckanovich, Ronald J; Sasaroli, Dimitra; O'Brien-Jenkins, Anne et al. (2007) Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol 25:852-61 |
| Coukos, George; Conejo-Garcia, Jose R; Buckanovich, Ron et al. (2007) Vascular leukocytes: a population with angiogenic and immunossuppressive properties highly represented in ovarian cancer. Adv Exp Med Biol 590:185-93 |
| Buckanovich, Ronald J; Sasaroli, Dimitra; O'brien-Jenkins, Ann et al. (2006) Use of immuno-LCM to identify the in situ expression profile of cellular constituents of the tumor microenvironment. Cancer Biol Ther 5:635-42 |
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