TY - JOUR
T1 - The ovarian cancer Chemokine landscape is conducive to homing of vaccine-primed and CD3/CD28-Costimulated T cells prepared for adoptive therapy
AU - Zsiros, Emese
AU - Duttagupta, Priyanka
AU - Dangaj, Denarda
AU - Li, Hongzhe
AU - Frank, Renee
AU - Garrabrant, Thomas
AU - Hagemann, Ian S.
AU - Levine, Bruce L.
AU - June, Carl H.
AU - Zhang, Lin
AU - Wang, Ena
AU - Marincola, Francesco M.
AU - Bedognetti, Davide
AU - Powell, Daniel J.
AU - Tanyi, Janos
AU - Feldman, Michael D.
AU - Kandalaft, Lana E.
AU - Coukos, George
N1 - Publisher Copyright:
© 2015 AACR.
PY - 2015/6/15
Y1 - 2015/6/15
N2 - Purpose: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)-vaccine primed T cells in the context of cell-based immunotherapy. Experimental Design: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer. Results: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumorinfiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer. Conclusions: DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines.
AB - Purpose: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)-vaccine primed T cells in the context of cell-based immunotherapy. Experimental Design: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer. Results: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumorinfiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer. Conclusions: DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines.
UR - http://www.scopus.com/inward/record.url?scp=84936890861&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-2777
DO - 10.1158/1078-0432.CCR-14-2777
M3 - Article
C2 - 25712684
AN - SCOPUS:84936890861
SN - 1078-0432
VL - 21
SP - 2840
EP - 2850
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -