Abstract
Dendritic cells (DCs) hold promise for anti-cancer immunotherapy. However, clinically, their efficiency is limited and novel strategies to improve DC-mediated anti-tumor responses are needed. Human DCs display high content of sialic acids, which inhibits their maturation and co-stimulation capacity. Here, we aimed to understand whether exogenous desialylation of DCs improves their anti-tumor immunity. Compared to fully sialylated DCs, desialylated human DCs loaded with tumor-antigens showed enhanced ability to induce autologous T cells to proliferate, to secrete Th1 cytokines, and to specifically induce tumor cell apoptosis. Desialylated DCs showed an increased expression of MHC-I and -II, co-stimulatory molecules and an augmented secretion of IL-12. Desialylated HLA-A*02:01 DCs pulsed with gp100 peptides displayed enhanced peptide presentation through MHC-I, resulting in higher activation ofgp100280–288 specific CD8+ cytotoxic T cells. Desialylated murine DCs also exhibited increased MHC and co-stimulatory molecules and higher antigen cross-presentation via MHC-I. These DCs showed higher ability to activate antigen-specific CD4+ and CD8+ T cells, and to specifically induce tumor cell apoptosis. Collectively, our data demonstrates that desialylation improves DCs' ability to elicit T cell-mediated anti-tumor activity, due to increased MHC-I expression and higher antigen presentation via MHC-I. Sialidase treatment of DCs may represent a technology to improve the efficacy of antigen loaded-DC-based vaccines for anti-cancer immunotherapy.
Highlights
Several studies have shown the potential of dendritic cells (DCs) as therapeutic vaccination against cancer.[1-4] only few vaccines have been approved for clinical use.[5]
Based on carboxyfluorescein succinimidyl ester (CFSE) dilution method, T cells primed with desialylated monocyte-derived DCs (MoDCs) showed higher proliferation, when compared to those primed with fully sialylated MoDCs (Figure 1A)
To further characterize the profile of T cells generated by desialylated MoDCs stimuli, the secretion of the Th1 cytokines - tumor necrosis factor (TNF)-α and IFN-γ - and of the Th2 cytokine - IL-4 - was analysed
Summary
Several studies have shown the potential of dendritic cells (DCs) as therapeutic vaccination against cancer.[1-4] only few vaccines have been approved for clinical use.[5]. Efficient www.impactjournals.com/oncotarget induction of anti-tumor responses requires that DCs undergo proper maturation. This process is characterized by: increased expression of major histocompatibility complex (MHC) molecules, needed to present antigens to T cells; increased expression of co-stimulatory molecules, such as CD80 and CD86, to promote DC interaction with T cells;[7] and secretion of pro-inflammatory cytokines, such as the Th1-inducing cytokine interleukin (IL)-12, required for anti-tumor activity.[8]. [2] Notably, DCs are endowed with a unique antigen processing pathway that enables exogenous antigens to undergo proteasomal degradation and be presented in the context of MHC-I molecules to CD8+ cytotoxic T cells, in a process called cross-presentation.[9, 10]. Since most tumor-associated antigens used for DC vaccination are of exogenous origin, strategies that foment antigen presentation through MHC-I are crucial for the generation of CD8+ cytotoxic T cell response, and thereby, for the generation of an anti-tumor immune response.[10, 12, 13]
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