The ovarian cancer Chemokine landscape is conducive to homing of vaccine-primed and CD3/CD28-Costimulated T cells prepared for adoptive therapy

Emese Zsiros, Priyanka Duttagupta, Denarda Dangaj, Hongzhe Li, Renee Frank, Thomas Garrabrant, Ian S. Hagemann, Bruce L. Levine, Carl H. June, Lin Zhang, Ena Wang, Francesco M. Marincola, Davide Bedognetti, Daniel J. Powell, Janos Tanyi, Michael D. Feldman, Lana E. Kandalaft, George Coukos

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Abstract

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.

Original languageEnglish
Pages (from-to)2840-2850
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number12
DOIs
Publication statusPublished - 15 Jun 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zsiros, E., Duttagupta, P., Dangaj, D., Li, H., Frank, R., Garrabrant, T., Hagemann, I. S., Levine, B. L., June, C. H., Zhang, L., Wang, E., Marincola, F. M., Bedognetti, D., Powell, D. J., Tanyi, J., Feldman, M. D., Kandalaft, L. E., & Coukos, G. (2015). The ovarian cancer Chemokine landscape is conducive to homing of vaccine-primed and CD3/CD28-Costimulated T cells prepared for adoptive therapy. Clinical Cancer Research, 21(12), 2840-2850. https://doi.org/10.1158/1078-0432.CCR-14-2777