Ovarian Tumor Ascites CD14+ Cells Suppress Dendritic Cell–activated CD4+ T-cell Responses Through IL-10 Secretion and Indoleamine 2,3-Dioxygenase

Abstract

The observation that Th17 infiltration in ovarian cancer correlates with markedly improved survival has prompted the question of whether ovarian tumor antigen-specific Th17 responses could be stimulated by tumor vaccination. Dendritic cells (DCs) treated with IL-15 and an inhibitor of p38 MAPK signaling (DC(IL-15/p38inhib)) bias T-cell responses toward a Th1/Th17 phenotype, raising the prospect of therapeutic vaccination; however, significant barriers remain. Tumor vaccines, including DC vaccination, usually stimulate immune responses, but the lack of clinical responses in cancer patients has been disappointing. Possible reasons may include an inability of antitumor T cells to migrate into the tumor microenvironment, and an inability of T cells to retain effector function in the face of tumor-associated immune suppression. We found that ovarian tumor antigen-specific CD4(+) T cells induced by DC(IL-15/p38inhib) migrated in response to CXCL12 and CCL22 (both highly expressed in ovarian cancer) and to ascites CD14(+) myeloid cells. Cocultures showed that ascites CD14(+) cells markedly suppressed antigen-specific CD4(+) T responses, but suppression could be alleviated by treatment with anti-IL-10 or inhibition of indoleamine 2,3-dioxygenase. These results suggest that the efficacy of DC vaccination against ovarian cancer may be boosted by agents that inhibit tumor-associated CD14(+) myeloid cell suppression or indoleamine 2,3-dioxygenase activity.