IL-10 in the microenvironment of HNSCC inhibits the CpG ODN induced IFN-α secretion of pDCs

Abstract

Abstract. It has been shown that head and neck squamous cell carcinoma (HNSCC) is infiltrated by plasmacytoid dendritic cells (pDCs). The HNSCC TH2 biased microenvironment leads to strong alterations of the cellular functions of pDC and thus impairs the initiation and function of adequate immune responses. In this work we comprehensively analyzed the capacity of CpG-oligonucleotides to activate interferon (IFN)-α secretion of human pDC in the presence of HNSCC. IFN-α secretion was measured using the ELISA Technique. Class A CpG dinucleotide 2216 was used in different concentrations and time frames to stimulate the IFN-α production of human pDC from peripheral blood in the absence and presence of the HNSCC microenvironment. To elucidate single components that might induce the reduction of IFN-α secretion, pDC were exposed to different concentrations of HNSCC relevant cytokines such as IL-6, IL-8 and IL-10. In accordance to former experiments we found that HNSCC micro milieu severely depresses up to 75% of IFN-α secretion capacity of pDCs, if the stimulating Class A CpG 2216 is added to the culture. Preincubation of HNSCC supernatant leads to unrestorable reduction of IFN-α secretion in pDC and can not be restored by CpG 2216. Incubation of pDCs with single cytokines relevant for cancer progression within the HNSCC micro milieu show that IL-6 or IL-8 have no influence on the IFN-α secretion in pDCs, whereas IL-10 massively impairs the secretion in a dose dependent manner. This effect can be potentiated by synergistic incubation with IL-6 and can be abrogated by blocking antibodies to the IL-10 receptor. Interestingly, incubation with IL-10 is not the only factor that impairs the IFN-α secretion, as incubation with the whole HNSCC supernatant is even more effective in reducing the secretion, implying that additional factors play a role. We conclude that restoration of HNSCC induced TH2 bias could be improved by the inhibition of immune cell cytokine receptors in addition to immunostimulating approaches with CpG motifs.

Immunology of Plasmacytoid Dendritic Cells in Solid Tumors: A Brief Review

“…The same author group later elucidated the underlying mechanism of impaired IFNα secretion, identifying prostaglandin E2 and TGFβ from HNSCC culture supernatants as the most important negative regulators of pDC functions [50]. Other research teams reported similar effects on IFNα secretion in the setting of HNSCC when blood-derived human pDCs were incubated with tumor supernatants [51,52]. Bruchhage et al also analyzed cytokines in HNSCC supernatants and tested their effect on pDCs.…”

A role for the immune system in advanced laryngeal cancer

“…Of note, head and neck squamous cell carcinoma is infiltrated by B cells (CD19, CD20) producing immunoglobulins and immature pDCs that can produce type I interferons (IFNs), including IFN-α, although why the association to CD19 with FCRLA or CD20 with FCRLA up-regulate the IFN-α, through pDCs, is not clear 39 , 47 , 48 . However, the type I IFNs could have significant antitumor efficacy, beyond the activation of the host innate immune response 49 – 51 .…”

Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

“…pDCs isolated from HNSCC tissues or exposed to HNSCC supernatants show an impaired IFN-α production upon CpG stimulation compared to blood-derived pDCs or pDCs exposed to control medium [131,140,173]. Tumor-induced down-regulation of TLR9 expression has been identified as one leading mechanism of pDC dysfunction within the tumor environment [140,142].…”

“…Tumor-induced down-regulation of TLR9 expression has been identified as one leading mechanism of pDC dysfunction within the tumor environment [140,142]. Furthermore, significant levels of PGE2, TGF-β and IL-10 are detected in the HNSCC and OSCC culture supernatants as mediators of IFN-α impairment in pDCs [140,142,161,173]. A decreased secretion of IFN-α, TNF-α, and IL-6 by tumor infiltrating pDCs was also detected in OSCC [141].…”