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upon the response to tumor therapy. The effectiveness of immune-based therapeutic strategies clearly
demonstrates the possibility of eradicating cancer through cellular immunity, particularly when active T
[1,3]
cells recognize cognate tumor antigens . Dendritic cells (DCs) have the capacity to prime naïve T cells
by inducing functional polarization, and are in charge of orchestrating the expansion and functions of T
cells and natural killer (NK) cells in lymphoid and non-lymphoid tissues of cancer patients. About 25 years
ago, some investigators put forward the concept of harnessing DC immunogenicity to induce protective
[4,5]
responses in cancer patients . Nevertheless, results have been far below expectations. These failures
occurred due to the almost exclusive usage of monocyte-derived cells (MoDCs) and tumor-associated
antigens. The advancement in basic understanding of the heterogeneity and functional plasticity of different
DC subsets suggests that conventional (classical) type 1 DCs (cDC1s) other than MoDCs may be better
suited for this purpose.

DENDRITIC CELL SUBSETS
Shortly after the discovery of DCs by Steinman in 1973, van Furth grouped them under the mononuclear
phagocyte system. Since then monocytes, macrophages and DCs have been grouped together, and they
[6]
are distinguished on the basis of their morphology, function and origin . However, lineage-tracing
studies by different groups demonstrate that most macrophages in adults are maintained independently
of blood monocytes and rely on self-renewal of embryonically derived macrophages under steady-state
[7,8]
conditions . The circulating monocytes could contribute to the expanding pool of macrophages in the
liver under inflammation status [9,10] . DCs arise from a common DC precursor in the bone marrow, and
their development depends on the cytokine Flt3L [11,12] . Although monocytes in some inflammation develop
[13]
to inflammatory DCs, termed IDCs , DCs are now generally grouped into conventional (classical) type 1
[14]
DCs (cDC1s), conventional type 2 DCs (cDC2s) and plasmacytoid DCs (pDCs) .

+
+
In mice, cDC1s include murine lymphoid CD8α DCs, migratory CD103 high DCs, and dermal CD207 DCs;
+
+
cDC2s include lymphoid CD4 DCs and migratory CD11b DCs; pDCs are IFN-producing DCs with the
[14]
cell surface markers B220, PDCA.1 and Ly6C . DCs have been divided into many different subsets based
on the expression of surface markers including CD40, CD11c, CD103 (integrin αE), CD11b (integrin αM),
F4/80, CD8α, CD24, CD172a (SIRPα and SHPS1), CX C-chemokine receptor 1 (CX CR1), XC-chemokine
3
3
[14]
receptor 1 (XCR1), CLEC9A (DNGR1), E-cadherin (cadherin 1) and CD64 (FcγRI) . Inflammation
further complicates the picture as mononuclear phagocytes in inflamed tissues undergo phenotypical
changes. Some researchers consider monocyte-derived cells as MoDCs or macrophages, based on CD11c
expression [13-15] . The analysis of gene expression profiles revealed that the gene transcripts in different
populations of macrophages are diverse, and some mRNA transcripts and surface proteins were selectively
[16]
expressed by macrophages but not DCs . Therefore, macrophages, monocytes and DCs are different cell
types with distinct ontogeny [7-14,16] .
DC-BASED CANCER VACCINES
DC-based cancer vaccines typically culture DCs with various tumor associated antigens ex vivo, such as
pulsing with peptides, whole proteins, tumor lysates, or fusion of DCs with entire tumor cells [1,4,5] . Most
+
DCs were generated from peripheral blood monocular cells (PBMCs)-derived CD14 monocytes or CD34 +
hematopoietic stem and progenitor cells via culturing with granulocyte-macrophage colony-stimulating
factor (GM-CSF) and interleukin 4 (IL-4). The efficacy of such vaccine formulations is suboptimal since the
[1,5]
macrophages were generated in culture with GM-CSF and its migratory capacity limited to lymph nodes .

To overcome these tedious processes and the uncertainty of quality, approaches that home antigens
directly to DCs in vivo via DC receptors were developed, such as antibodies against DEC-205, Clec9A and
Clec12A [1,4,17,18] . By using model antigens, i.e., OVA, or antigens from microbial products, direct targeting