While both DC populations effectively primed CD8+ T cell responses to cell-associated antigens, only mcDC were capable to prime CD4+ T cells to cell-associated antigens. Consequentially, the transfer of tumour vaccine-pulsed mcDC, but not of CD8 DCs, protected mice from subsequent tumour challenge in a vaccination model and resulted in eradication

of established tumours in a therapeutic mTOR inhibitor approach. These results show that the beneficial effect of FLT3L is associated with the induction of mcDC and suggests that selective targeting to mcDC or instilling mcDC ‘characteristics’ into conventional DC populations could significantly enhance the efficacy of tumour vaccines. Autologous tumour cell vaccines are intended to drive specific activation of the adaptive immune system for therapy of existing malignancies. The resulting in vivo destruction of tumour cells leads to an additional release of tumour antigens that further amplifies tumour-specific T cell responses [1–3]. This secondary antigenic boost has been suggested to help to enhance and sustain anti-tumour T cell responses and prevent recurrences and metastases. Dendritic cells (DC) are the only antigen-presenting cells that can adequately prime naive T cells.

The (cross)-presentation of tumour antigens by DC upon uptake of dying tumour cells/tumour cell debris has also been shown to be critical for the induction of endogenous anti-tumour T cell responses [4,5]. DCs are phenotypically and functionally heterogeneous. MLN0128 concentration At least six DC subsets have been described in mice and Erastin humans: plasmacytoid DCs (pDCs), three blood-derived subsets (CD4+ DCs, CD8α+ DCs and CD4-CD8- DCs [6,7]) and two tissue-derived subsets (Langerhans’ cells and dermal/interstitial DCs)

– all of which appear to be distinct sublineages and not precursor-product-related [8–10]. However, this classification has been proved to be a simplified subdivision, as we and others have recently identified novel DC subsets that are either present in common lymphoid tissues or associated with specific organs [11–15]. Even though most DC subsets can capture proteins and cell-associated antigens and can activate CD4+ and CD8+ T cells when pulsed with cognate peptides, only few DC populations have the actual capacity to process and present tumour-derived antigens to T cells [16,17]. Cross-presentation of cell-associated antigens to CD8+ T cells in particular is believed to be limited to just one or two DC populations [17,18]. Moreover, besides the fact that only few DC subsets can present both CD4+ and CD8+ T cell epitopes from cell-associated antigens, both human and mouse studies have shown that detection and subsequent clearance of apoptotic cells leads to a tolerogenic state in DC [19–22].