The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28–Costimulated T Cells Prepared for Adoptive Therapy

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. Clin Cancer Res; 21(12); 2840-50. Ó2015 AACR.

The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1 −/− murine model of ovarian cancer

“…Representative figures of flow cytometric analysis of CD4 þ T cells, CD8 þ T cells, B cells, NK cells, CD4 þ regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are shown in Fig. 3A Recently, it has been shown that high expression of the lymphocyte-recruiting chemokines CCL2 and CCL5 is associated with the presence of TILs in ovarian cancer [16]. For this reason, we hypothesized that BMN 673 may induce the expression of these chemokines.…”

Ovarian cancer chemokines may not be a significant barrier during whole tumor antigen dendritic-cell vaccine and adoptive T-cell immunotherapy

“…6 Our results demonstrated that the chemokine landscape of ovarian cancer is heterogeneous with high expression levels of known lymphocyte-recruiting chemokines. For instance, tumors with pre-existing tumor-infiltrating intraepithelial T cells expressed high levels of CCL2, CCL4, CCL5 and CCL8 in tumor islets.…”

“…Furthermore, we confirmed that these receptors were functional and specified T cell migration toward their cognate chemokines. 6 The above results indicate that although many ovarian cancers do not exhibit intraepithelial T cells, they do express some chemokines within the tumor islets that could support T-cell homing and engraftment. Additional work is required to understand whether these "quasi-universal" chemokines are indeed functional and the mechanisms underlying the lack of intraepithelial T cells in these tumors despite the expression of such chemokines.…”

“…On the other hand, CXCL10, CXCL12 and CXCL16 were expressed quasi-universally in nearly all tumors, including tumors lacking intraepithelial T cells. 6 Importantly, the chemokine milieu in metast atic deposits resembled the primary site, suggesting minimal heterogeneity. 6 Immunotherapy approaches for patients with recurrent ovarian cancer remain limited.…”

“…6 Importantly, the chemokine milieu in metast atic deposits resembled the primary site, suggesting minimal heterogeneity. 6 Immunotherapy approaches for patients with recurrent ovarian cancer remain limited. Anti-cancer vaccination using a whole tumor lysate dendritic-cell (DC) vaccine approach to multiple tumor-associated antigens has proven a useful strategy to elicit or enhance antitumor immune responses, particularly prior to adoptive cell transfer.…”