Dendritic Cell Immunotherapy for the Treatment of Neoplastic Disease William K. Decker, Dongxia Xing, Elizabeth J. Shpall  Biology of Blood and Marrow Transplantation  Volume 12, Issue 2, Pages 113-125 (February 2006) DOI: 10.1016/j.bbmt.2005.09.003 Copyright © 2006 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 The life cycle of a myeloid (DC1) dendritic cell (DC). Immature DCs are very efficient in antigen uptake and processing. Antigens are taken up by scavenger receptors or by macropinocytosis (a). Next to the common pathways for MHC class I and II–restricted antigen presentation, DCs are unique in that exogenous antigens may access the class I pathway (b). This process is referred to as cross-presentation. Inflammatory agents induce the migration of the immature dendritic cell into the T-cell areas of secondary lymphoid organs. This migratory process (c) is controlled by different subsets of chemokine receptors and is aided by the secretion of metalloproteases, which degrade the extracellular matrix. T-cell activation units (d), consisting of peptide-loaded MHC class II and co-stimulatory molecules such as B7, are displayed after maturation on the DC, where they may constitute part of the immunologic synapse. Mature DCs also secrete several chemokines and cytokines, whose activity is modulated by proteases and protease inhibitors (e). ER indicates endoplasmic reticulum; MHC, major histocompatibility complex; MIIC, MHC class II compartment; TAP, transporter associated with antigen processing. Figure reproduced from Hartgers et al. [9] with permission. Biology of Blood and Marrow Transplantation 2006 12, 113-125DOI: (10.1016/j.bbmt.2005.09.003) Copyright © 2006 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Subsets of human dendritic cells (DCs). Blood DCs, mobilized by Flt-3 ligand, contain both CD11c+ myeloid DCs (MDCs) and CD11c− plasmacytoid DCs (PDCs). Most clinical studies to date have been performed with DCs made by culturing monocytes with GM-CSF and IL-4. These preparations contain cells that resemble interstitial DCs and are devoid of Langerhans cells. These DCs are immature and require exogenous factors for maturation. Myeloid DCs can also be generated by culturing CD34+ hematopoietic precursor cells (HPCs) with GM-CSF and TNF-α, thus allowing the derivation of each myeloid DC subset. A distinct subset of precursors, CD34+CD45RA+, gives rise in vitro to plasmacytoid DCs upon culture with Flt-3 ligand. Figure reproduced from Banchereau et al. [8] with permission. Biology of Blood and Marrow Transplantation 2006 12, 113-125DOI: (10.1016/j.bbmt.2005.09.003) Copyright © 2006 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Loading and presentation of MHC class I and MHC class II antigens by dendritic cells. Antigens external to the dendritic cell are phagocytosed or taken up by receptor-mediated endocytosis. Once internalized, these exogenous antigens are degraded in the lysosomal compartment, loaded onto empty MHC class II molecules, and presented on the cell surface, where they may prime a cognate CD4+ T cell (left). Dendritic cells also possess the ability to present some exogenously derived class II antigens on MHC class I by a poorly characterized mechanism termed cross-presentation. Internal dendritic cell antigens, such as those present endogenously or, eg, by mRNA transfection or viral infection, are constitutively degraded at a basal level by the proteasome. Degradation products are processed in the endoplasmic reticulum, loaded onto MHC class I, and transported to the cell surface for priming of cognate CD8+ T cells (right). During the loading of dendritic cell vaccines with peptides, the peptide antigens are thought to mainly bind empty MHC class I and class II molecules on the cell surface without being internally processed by the dendritic cell. MHC indicates major histocompatibility complex; MIIC, MHC class II compartment; TAP, transporter associated with antigen processing. Biology of Blood and Marrow Transplantation 2006 12, 113-125DOI: (10.1016/j.bbmt.2005.09.003) Copyright © 2006 American Society for Blood and Marrow Transplantation Terms and Conditions