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 to could be stimulated by tumor vaccination. Dendritic cells treated with IL-15 and an inhibitor of p38 MAPK signaling (DCIL-15/p38inhib) bias T cell responses toward a Th1/Th17 phenotype, raising the prospect of therapeutic vaccination, but 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 anti-tumor 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 DCIL-15/p38inhib migrated in response to CXCL12 and CCL22 (both highly expressed in ovarian cancer), and 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 (IDO). 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 IDO activity.

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

“…[9][10][11][12][13][14] For many of these tumors, elevated intratumoral CCL22 concentrations are associated with a higher tumor infiltration by Treg. Treg are an inhibitory subset of T helper cells, whose function is to suppress cytotoxic T effector cell functions, [15][16][17] involving cell-contact dependent and cell-contact independent mechanisms such as consumption of IL-2, expression of the cellsurface antigen CTLA-4 and secretion of inhibitory cytokines such as TGF-b and IL-10. [18][19][20][21] Treg have been found to accumulate in tumor tissues as well as in tumor-draining lymph nodes, malignant ascites and peripheral blood of tumor patients.…”

VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells

“…Identification of immunosuppressive factors produced within the tumor microenvironment, and the ability to target these factors could enhance anti-tumor immune responses. Several studies have focused on tumor-associated immune suppression mediated by T regulatory (Treg) cells, myeloid derived suppressor cells (MDSC), immunosuppressive dendritic cells, immune-inhibitory receptors, and inhibitory factors, including TGF-β, prostaglandins, and adenosine (12-17). In addition, components of ovarian ascites fluid have also been shown to inhibit immune function (18).…”

Myxoma Virus Optimizes Cisplatin for the Treatment of Ovarian Cancer In Vitro and in a Syngeneic Murine Dissemination Model

“… 36 The ability of CD14 + myeloid cells to produce IL-10 has a suppressive effect on T cells present in the OC tumor environment in the peritoneal cavity. 37 , 38 MYXV preferentially binds and enters human CD14 + cells rather than other immune cells to initiate early gene expression without resulting in a productive infection. 29 We found that MYXV did not affect the general viability of healthy human CD14 + cells.…”

“…OC tumor-associated CD14 + monocytes were purified from patient ascites as described previously. 38 Briefly, primary ovarian tumor ascites CD14 + cells were separated magnetically using commercially available columns and anti-CD14 conjugated microbeads (Miltenyi Biotec, Auburn, CA), according to the manufacturer’s instructions. The purity of recovered ascites CD14 + cells was typically 95%–98%.…”