Genomic instability of ovarian cancer (OvCa) cells and the resulting frequent loss or reduction of HLA expression and function facilitate immune avoidance of this aggressive cancer. The goal of this Project is to develop an effective mode of immunotherapy capable of targeting both MHC-positive and MHC-negative variants of OvCa and counteracting local immune suppression, known to contribute to poor prognosis in OvCa patients. We observed that type-1-polarized DCs (?DC1s), a novel type of DCs developed by our group, effectively cross-present OvCa-related antigens and induce high numbers of MHC class l-restricted CTLs capable of recognizing defined OvCa-related antigenic epitopes. However aDC1-induced CTLs also express elevated levels of NK receptors, NKG2D- and DNAM1. Such

Public Health Relevance

We plan to develop a new immunotherapy of ovarian cancer, combining a new highly-potent autologous dendritic cells vaccine (?DC1s) with the local infusion of ex-vivo ?DC1-induced effector CD8+ T cells (CTLs) able of recognizing tumor cells both in a classical (TCR-dependent) and TCR-independent manner. We anticipate that such treatment will promote destruction of residual tumor cells in patients with advanced ovarian cancer treated with chemotherapy, independently on their ability to mutate and evade classical forms of immune recognition, preventing or delaying tumor recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA159981-01A1
Application #
8485810
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (J1))
Project Start
2013-09-18
Project End
2018-06-30
Budget Start
2013-09-18
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$252,036
Indirect Cost
$41,459
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Gil, Margaret; Komorowski, Marcin P; Seshadri, Mukund et al. (2014) CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. J Immunol 193:5327-37
Eng, Kevin H; Ruggeri, Christina (2014) Connecting prognostic ligand receptor signaling loops in advanced ovarian cancer. PLoS One 9:e107193
Liao, Jianqun; Qian, Feng; Tchabo, Nana et al. (2014) Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS One 9:e84941
Suryawanshi, Swati; Huang, Xin; Elishaev, Esther et al. (2014) Complement pathway is frequently altered in endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res 20:6163-74
Matsuzaki, Junko; Tsuji, Takemasa; Luescher, Immanuel et al. (2014) Nonclassical antigen-processing pathways are required for MHC class II-restricted direct tumor recognition by NY-ESO-1-specific CD4(+) T cells. Cancer Immunol Res 2:341-50
Daudi, Sayeema; Eng, Kevin H; Mhawech-Fauceglia, Paulette et al. (2014) Expression and immune responses to MAGE antigens predict survival in epithelial ovarian cancer. PLoS One 9:e104099