Abstract
BackgroundDendritic cells (DCs) are professional antigen presenting cells that initiate specific immune responses against tumor cells. Transcription factor RBP-J-mediated Notch signaling regulates DC genesis, but whether this pathway regulates DC function in anti-tumor immunity remains unclear. In the present work we attempted to identify the role of Notch signaling in DC-mediated anti-tumor immune response.ResultsWhen DCs were co-inoculated together with tumor cells, while the control DCs repressed tumor growth, the RBP-J deficient DCs had lost tumor repression activity. This was most likely due to that DCs with the conditionally ablated RBP-J were unable to evoke anti-tumor immune responses in the solid tumors. Indeed, tumors containing the RBP-J deficient DCs had fewer infiltrating T-cells, B-cells and NK-cells. Similarly, the draining lymph nodes of the tumors with RBP-J-/- DCs were smaller in size, and contained fewer cells of the T, B and NK lineages, as compared with the controls. At the molecular level, the RBP-J deficient DCs expressed lower MHC II, CD80, CD86, and CCR7, resulting in inefficient DC migration and T-cell activation in vitro and in vivo. T-cells stimulated by the RBP-J deficient DCs did not possess efficient cytotoxicity against tumor cells, in contrast to the control DCs.ConclusionThe RBP-J-mediated Notch signaling is essential for DC-dependent anti-tumor immune responses. The deficiency of RBP-J impairs the DC-based anti-tumor immunity through affecting series of processes including maturation, migration, antigen presentation and T-cell activation. The Notch signaling pathway might be a target for the establishment of the DC-based anti-tumor immunotherapies.
Highlights
Dendritic cells (DCs) are professional antigen presenting cells that initiate specific immune responses against tumor cells
The tumor infiltrating myeloidderived suppressor cells (MDSCs), the tumor-associated macrophages (TAMs) [11,12] and the cytokines secreted by MDSCs and TAMs cooperatively create an immunosuppressive environment which leads to the suppression of DC functions and the induction of regulatory T-cells
DCs have been considered as a promising agent to generate effective anti-tumor immune therapies, because DCs can be generated in large numbers, and the cultured immature DCs could be converted into mature DCs through the antigen loading with peptides, recombinant proteins, tumor antigen-encoding mRNA, and whole tumor cell lysates
Summary
Dendritic cells (DCs) are professional antigen presenting cells that initiate specific immune responses against tumor cells. Gerner et al reported that murine tumors were extensively infiltrated by partially activated tumor-infiltrating DCs (TIDCs) which had inefficient MHC II presentation due to poor intrinsic protein uptake capability, resulting in the inferior initiation of T-cell responses in the draining lymph nodes [13]. These resting, non-activated, immature phenotypes of DCs have been discovered in cancer patients [14]. The fully understanding of the molecular mechanisms regulating DC maturation and activation, which is still obscure, is a prerequisite for the DC-based anti-tumor therapies
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