serval:BIB_87A4CCCAC4DE
The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy.
10.1158/1078-0432.CCR-14-2777
000357336600024
25712684
Zsiros
E.
author
Duttagupta
P.
author
Dangaj
D.
author
Li
H.
author
Frank
R.
author
Garrabrant
T.
author
Hagemann
I.S.
author
Levine
B.L.
author
June
C.H.
author
Zhang
L.
author
Wang
E.
author
Marincola
F.M.
author
Bedognetti
D.
author
Powell
D.J.
author
Tanyi
J.
author
Feldman
M.D.
author
Kandalaft
L.E.
author
Coukos
G.
author
article
2015
Clinical Cancer Research
1078-0432
1078-0432
journal
21
12
2840-2850
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 tumor-infiltrating 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. Clin Cancer Res; 21(12); 2840-50. ©2015 AACR.
Antigens, CD28/metabolism
Antigens, CD3/metabolism
Biomarkers
Cancer Vaccines/immunology
Chemokines/genetics
Chemokines/metabolism
Chemotaxis, Leukocyte
Cluster Analysis
Dendritic Cells/immunology
Dendritic Cells/metabolism
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Immunotherapy, Adoptive
Neoplasm Grading
Neoplasm Staging
Ovarian Neoplasms/diagnosis
Ovarian Neoplasms/genetics
T-Cell Antigen Receptor Specificity/immunology
T-Lymphocyte Subsets/immunology
T-Lymphocyte Subsets/metabolism
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't Publication Status: ppublish
University of Lausanne
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