Dendritic Cell Vaccines for Cancer Immunotherapy: The Role of Human Conventional Type 1 Dendritic Cells

Abstract

Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Therefore, a great effort has been made to identify DC subsets with superior features for the establishment of effective anti-tumor responses and to apply them in therapeutic approaches. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response. Here, we sought to revise the immunobiology of cDC1 from their ontogeny to their development, regulation and heterogeneity. We also address the role of this functionally thrilling DC subset in anti-tumor immune responses and the most recent efforts to apply it in cancer immunotherapy.

Keywords: CD141+XCR1+ DCs; anti-tumor immunotherapy; conventional type 1 dendritic cells; dendritic cell-based vaccines.

Figure 1

Schematic representation of cDC1 DC development. In the bone marrow, HSC gives rise to the LMPP, which settles at the apex of all myeloid and lymphoid lineages and is separated from the MkE. GMDP derives from the LMPP and produces the MDP (expressing M-CSFR), which further differentiates into the CDP, capable of generating the main DC subsets: pDCs, cDC1 and cDC2. pDCs terminally differentiate in the bone marrow, whereas pre-cDC migrate through the blood to lymphoid and non-lymphoid tissues, where they produce cDC1 and cDC2 subsets. Determining the differentiation pathway, Notch-dependent interactions of CDPs with stromal cells, in cooperation with GM-CSF, are crucial for the commitment to the cDC1 lineage, separating their pathway from pDCs. In peripheral tissues, the differentiation into CD141⁺ cDC1 is controlled by transcription factors, such as IRF8, Batf3 and Id2 (shown in blue). After engagement with the CD141⁺ pathway, the existence of a two-staged differentiation process of cDC1 populations is proposed, in which XCR1-negative cDC1s under the influence of GM-CSF (shown in red) acquire the expression of XCR1, representing the shift between a pre-cross-presentation phase and a subsequential cross-presenting stage. cDC, conventional dendritic cell; CDP, common DC precursor; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; GMDP, granulocyte macrophage DC progenitor; HSC, hematopoietic stem cell; LMPP, lymphoid-primed multipotent progenitor; M-CSFR, macrophage colony-stimulating factor receptor; MDP, macrophage DC precursor; MkE, megakaryocyte and erythroid potential; pDC, plasmacytoid dendritic cell.

Figure 2

cDC1 interplay with CD8+ T and NK cells to develop anti-tumor responses. NK and CD8⁺ T cells express XCL1, which attracts XCR1⁺ cDC1 into the tumor microenvironment. In addition, NK cells can also produce CCL5, helping to recruit this subset of DCs. In turn, cDC1 are the main source of the chemokines CXCL9 and CXCL10, chemoattractants for T and NK cells. Functionally, cDC1 are highly capable of cross-presenting tumor antigens via MHC-I to CD8⁺ T cells and producing IL-12, which promotes T cell cytotoxicity and the production of INF-γ by NK cells. Furthermore, NK cells produce Flt3L that holds up the viability and functional capacities of cDC1 within the tumor microenvironment and can also promote their local differentiation from recruited precursors. cDC1, classical dendritic cell 1; Flt3L, FMS-like tyrosine kinase 3 ligand; IFN-γ, interferon gamma; MHC-I, major histocompatibility complex I; NK, natural killer; TCR, T cell receptor; XCL1, X-C Motif Chemokine Ligand 1.

Figure 3

Summary of current approaches exploring cDC1 in immunotherapy. To overcome the scarcity of natural circulating XCR1⁺ DCs, which hampers their clinical application, new protocols have allowed their ex vivo generation from CD34⁺ precursors and iPSCs and their reprograming from fibroblasts. As the resulting cells excel at the cross-presentation and generation of CTL responses, they allow for the formulation of innovative DC-based vaccines, where antigen loading with different TAAs and promising neoantigens potentially generate superior outcomes. Endogenous cDC1 can also be in vivo targeted by using carriers such as XCL1 or monoclonal antibodies to deliver antigens in a specific manner. Likewise, autologous and allogeneic tumor cells can be genetically engineered to express XCL1 and target XCR1⁺ DCs. Furthermore, IFN-α-iPSC-pMCs can potentiate XCR1⁺ DC activity by releasing IFN-α in vivo. Additionally, biomaterial-based scaffolds can be designed to release factors that recruit and activate DCs. These strategies aim to boost antigen-specific CD8⁺ T clone proliferation and responses, as well as enhance CD4⁺ T and NK cell activity. All these approaches can be potentially combined with conventional cancer therapeutics, namely radiotherapy and chemotherapy, but also with more recently developed immunotherapy strategies, such as immune checkpoint inhibitors. cDC1, Classical dendritic cell 1; CTL, cytotoxic T lymphocyte; DCs, dendritic cells; IFN-α, interferon alpha; IFN-α-iPSC-pMCs, IFN-α producing induced pluripotent stem-cell-derived proliferating myeloid cells; iPSCs, induced pluripotent stem-cells; NK, natural killer; TAAs, tumor-associated antigens; XCL1, X-C Motif Chemokine Ligand 1.