Primary Human Blood Dendritic Cells for Cancer Immunotherapy-Tailoring the Immune Response by Dendritic Cell Maturation

Abstract

Dendritic cell (DC)-based cancer vaccines hold the great promise of tipping the balance from tolerance of the tumor to rejection. In the last two decades, we have gained tremendous knowledge about DC-based cancer vaccines. The maturation of DCs has proven indispensable to induce immunogenic T cell responses. We review the insights gained from the development of maturation cocktails in monocyte derived DC-based trials. More recently, we have also gained insights into the functional specialization of primary human blood DC subsets. In peripheral human blood, we can distinguish at least three primary DC subsets, namely CD1c⁺ and CD141⁺ myeloid DCs and plasmacytoid DCs. We reflect the current knowledge on maturation and T helper polarization by these blood DC subsets in the context of DC-based cancer vaccines. The maturation stimulus in combination with the DC subset will determine the type of T cell response that is induced. First trials with these natural DCs underline their excellent in vivo functioning and mark them as promising tools for future vaccination strategies.

Keywords: CD141+ myeloid DC (mDC); CD1c+ mDC; DC-based cancer vaccines; human blood DC (dendritic cell) subsets; maturation; myeloid DC; plasmacytoid DC.

Figure 1

Maturation of moDCs and primary human DCs in the context of cancer immunotherapy. Stimulatory signals for human primary blood DCs include PAMPs from bacteria and viruses, but also proinflammatory cytokines. For cancer vaccine purposes, they can be matured by synthetic TLR ligands imitating natural ligands of TLRs. Monocyte-derived DCs used for DC-cell based cancer therapy are matured by proinflammatory cytokines or TLR ligands. TLR ligands mimicking viral infections—such as polyI:C (TLR3), R848 (TLR7/8) and CpG (TLR9)—have been proven most successful in inducing potent cellular responses. They trigger TLRs and induce maturation of the DCs; this increases expression of MHC and co-stimulatory molecules (not depicted) which support efficient T cell activation by the DCs. All subsets can cross-present antigen to CD8⁺ T cells and will direct T cell responses by soluble factors. Chemoattractants for immune cells are produced by all subsets. Plasmacytoid DCs are potent inducers of type I IFNs, which have pleiotropic effects on many cell types including T cells, NK cells and mDCs (cross-talk). Monocyte-derived DCs, CD1c⁺ mDCs and CD141⁺ mDCs produce IL-12, supporting CD4⁺ T cell skewing towards a T helper type 1 (Th1) phenotype. Mature CD141⁺ mDCs also produce IFN-λ, further supporting Th1 skewing. NK cells, activated produce chemokine (C motif) ligand 1 (XCL1), a chemokine sensed by CD141⁺ mDCs expressing its receptor chemokine (C motif) receptor 1 (XCR1). NK cells thereby attract CD141⁺ mDCs that are equipped to take up and (cross-) present dead cell material and initiate adaptive cellular T cell responses. Together, these functions of mature human moDCs and blood DCs allow the induction of potent cellular anti-tumor responses.