Psoriasis vulgaris is an inflammatory skin disease caused by hyper-activated T-cells regulated by positive and negative mechanisms; while the former has been much studied, but the latter has not. We studied the regulatory mechanism mediated by myeloid-derived suppressor cells (MDSCs), especially having shown that MDSCs expanded in melanoma patients express DC-HIL, a critical mediator of T-cell suppressor function. We examined expansion of DC-HIL+ MDSCs in psoriasis and characterized their functional properties. Frequency of DC-HIL+ monocytic MDSCs (CD14+HLA-DRno/low) in blood and skin was markedly increased in psoriatic patients vs. healthy controls, but there was no statistically significant relationship with disease severity (PASI score). Blood DC-HIL+ MDSC levels in the untreated patients were significantly higher than the treated patients. Compared to melanoma-derived MDSCs, psoriatic MDSCs exhibited significantly reduced suppressor function, and were less dependent on DC-HIL, but capable of inhibiting proliferation and IFN-γ and IL-17 responses of autologous T-cells. Psoriatic MDSCs were functionally diverse among patients in their ability to suppress allogeneic T-cells and use of either IL-17/arginase I or IFN-γ/iNOS axis as suppressor mechanisms. Thus DC-HIL+ MDSCs are expanded in psoriasis patients, and their mechanistic heterogeneity and relative functional deficiency may contribute to the development of psoriasis.
Purpose: Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness.Experimental Design: Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (n ¼ 76) at baseline and/or follow-up after ICI monotherapy. Bloodsoluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-DC-HIL gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression.Results: Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (n ¼ 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL þ MDSC or induction of sDC-HIL expression.Conclusions: sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.
Epidermal Langerhans cells (LC) belong to the antigen‐presenting cell (APC) family of dendritic cells that can initiate antigen‐specific immunogenic or tolerogenic responses. In mice, we have shown ultraviolet‐B (UV‐B) irradiation to induce long‐lasting suppression (tolerance) of contact hyper‐sensitivity responses by converting LC from immunogenic to tolerogenic APC. The C‐type lectin receptor, dectin‐2, expressed preferentially by LC and dendritic cells, has also been shown to be involved in inducing this form of UV‐B‐induced immunosuppression. These observations led us to question whether UV‐B can modulate dectin‐2 expression by LC. In ICR mice engineered to express the dectin‐2 gene promoter linked to a luciferase reporter gene, we found broadband UV‐B treatment in vivo to activate the promoter in LC. In wild‐type C3H/HeN mice, we found such treatment in vivo to yield LC with increased dectin‐2 expression at both mRNA and protein levels. Broadband UV‐B treatment in vitro of bone marrow‐derived dendritic cells from these mice also showed upregulated expression of dectin‐2 mRNA. These findings lead us to conclude that broadband UV‐B upregulates dectin‐2 expression in LC by activating the dectin‐2 gene promoter. Such amplification suggests that UV‐B‐induced immunosuppression may be due (at least in part) to augmented dectin‐2 expression in LC.
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