Prostanoids Play a Major Role in the Primary Tumor-Induced Inhibition of Dendritic Cell Differentiation

Abstract

Production of immunosuppressive factors is one of the mechanisms by which tumors evade immunosurveillance. Soluble factors hampering dendritic cell (DC) development have recently been identified in culture supernatants derived from tumor cell lines. In this study, we investigated the presence of such factors in 24-h culture supernatants from freshly excised solid human tumors (colon, breast, renal cell carcinoma, and melanoma). While primary tumor-derived supernatant (TDSN) profoundly hampered the in vitro DC differentiation from CD14+ plastic-adherent monocytes or CD34+ precursors (based on morphology and CD1a/CD14 phenotype), the effects of tested tumor cell line-derived supernatants were minor. Cyclooxygenase (COX)-1- and COX-2-regulated prostanoids present in the primary TDSN were found to be solely responsible for the observed hampered differentiation of monocyte-derived DC (MoDC). In contrast, both prostanoids and IL-6 were found to contribute to the TDSN-induced inhibition of DC differentiation from CD34+ precursor cells. While the addition of TDSN during differentiation interfered with the ability of CD34-derived DC to stimulate a primary allogeneic T cell response, it actually increased this ability of MoDC. These opposite effects were correlated to different effects of the TDSN on the expression levels of CD86 and HLA-DR on the DC from the different precursor origins. Although TDSN increased the T cell-stimulatory capacity of MoDC, TDSN inhibited the IL-12 production and increased the IL-10 production of MoDC, thus skewing them to a type-2 T cell-inducing phenotype. In conclusion, this study demonstrates that primary tumors negatively impact DC development and function through COX-1 and -2 regulated factors, whereas tumor-derived cell lines may lose this ability upon in vitro propagation.

Human Papillomavirus Type 16-Positive Cervical Cancer Is Associated with Impaired CD4+ T-Cell Immunity against Early Antigens E2 and E6

“…The discrepancy between the character of MRM-specific responses on one hand and mitogen-triggered and HPV-specific responses on the other can most readily be explained by the fact that MRM-specific T-cell memory was established and therefore properly polarized before the development of cervical neoplasia. These strongly polarized MRM-specific memory T cells are, in contrast to naïve T cells, relatively insensitive to modified antigen-presenting cell function (35,36), such as that expected to be found in cervical cancer patients (37). Mitogen-induced cytokine secretion, on the other hand, reflects the cytokine production of all peripheral T cells, including that of naïve T cells and those that have been primed against other pathogens during this period of HPVinduced disease.…”

Cyclic Nucleotides Promote Monocyte Differentiation Toward a DC-SIGN+ (CD209) Intermediate Cell and Impair Differentiation into Dendritic Cells

“…Cells exposed to PGE 2 during differentiation also lost the ability to produce IL-12, suggesting that cAMP inducers have the potential to skew the immune response toward Th2 immunity. Recently, Sombroek et al (21) reported that high concentrations of PGE 2 produced by primary tumors play a major role in tumorinduced inhibition of DC differentiation. Neither of these studies addressed the intracellular mechanism operating downstream of PGE 2 .…”

Generation of functional monocyte-derived fast dendritic cells suitable for clinical application in the absence of interleukin-6

“…DCs (Kalinski et al 1998). Although the aforementioned cytokines were capable of inducing DCs maturation, they inhibited DCs differentiation from Mo (Motta et al 2010;Sallusto and Lanzavecchia 1994;Sombroek et al 2002). Addition of TNF-a, IL-1b or IL-6 to Mo cultures prevented the loss of CD14 as well as the appearance of CD1a molecules, and hence suppressed the in vitro generation of CD14 -CD1a…”

“…The inhibition of DCs development may be a way to ensure tumour cell survival, as the immune response becomes compromised (Motta et al 2010). Indeed, it was found that IL-1b and PGE 2 produced by tumour cells inhibited the Mo differentiation into immature DCs (Motta et al 2010;Sombroek et al 2002). Also, IL-6 secreted by human pancreatic cancer cells suppressed the generation of DCs from Mo via aberrant activation of signal transducer and activator of transcription 3, which may represent a novel target for the prevention of unwanted immune responses in autoimmune diseases through the control of DCs differentiation (Bharadwaj et al 2007;Park et al 2004).…”