Abstract
BackgroundTumor-associated dendritic cells (TADCs) can interact with tumor cells to suppress anti-tumor T cell immunity. However, there is no information on whether and how TADCs can modulate programmed death-ligand 1 (PD-L1) expression by cancer cells.MethodsHuman peripheral blood monocytes were induced for DCs and immature DCs were cultured alone, or co-cultured with bladder cancer T24 or control SV-HUC-1 cells, followed by stimulating with LPS for DC activation. The activation status of DCs was characterized by flow cytometry and allogenic T cell proliferation. The levels of chemokines in the supernatants of co-cultured DCs were measured by CBA-based flow cytometry. The impacts of CXCL9 on PD-L1, STAT3 and Akt expression and STAT3 and Akt phosphorylation in T24 cells were determined by flow cytometry and Western blot.ResultsCompared with the control DCs, TADCs exhibited immature phenotype and had significantly lower capacity to stimulate allogenic T cell proliferation, particularly in the presence of recombinant CXCL9. TADCs produced significantly higher levels of CXCL9, which enhanced PD-L1 expression in T24 cells. Pre-treatment with AMG487 abrogated the CXCL9-increased PD-L1 expression in T24 cells. Treatment with CXCL9 significantly enhanced STAT3 and Akt activation in T24 cells.ConclusionsTADCs produced high levels of CXCL9 that increased PD-L1 expression in bladder cancer T24 cells by activating the CXCR3-related signaling. Our findings may shed new lights in understanding the regulatory roles of TADCs in inhibiting antitumor T cell responses and promoting tumor growth.
Highlights
Tumor-associated dendritic cells (TADCs) can interact with tumor cells to suppress anti-tumor T cell immunity
Co-culture of immature Dendritic cells (DCs) with bladder cancer T24 cells inhibits DC activation induced by lipopolysaccharide (LPS) We first induced human monocytes into immature DCs, which were co-cultured with, or without, T24 or SVHUC-1 for 24 h, followed by stimulating with LPS for DC activation for 24 h
We found that control DCs stimulated strong T cell proliferation, which was significantly mitigated by addition of T24 cells and further reduced by addition of CXCL9treated T24 cells (p < 0.05, Fig. 1c and d)
Summary
Tumor-associated dendritic cells (TADCs) can interact with tumor cells to suppress anti-tumor T cell immunity. Dendritic cells (DCs) are the most potent antigenpresenting cells to induce an antigen-specific anti-tumor immunity [1]. DCs in a tumor environment usually display suppressive and dysfunctional phenotypes, which contribute to the evasion of cancer cells from host immunosurveillance [2]. Tumor-associated DCs (TADCs) can secrete numerous types of cytokines, such as IL-10 and TGF-β1 that inhibit T cell activation and promote tumor cell growth [3]. IL-10 secreted by tolerized or type 2 DCs suppresses effector T cell function and cytotoxic lymphocyte response [4]. The function of TADCs in the growth of tumors and chemokine expression has not been fully understood
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