Dendritic Cells and Cancer: Prospects for Cancer Vaccination

Abstract

Effective therapeutic cancer vaccination is an old dream, now rekindled by modern advances in cell biology and immunology. Several key facts have inspired the current optimism for clinical immunotherapy trials. First, the realization that, by definition, every malignant cell must express at least one gene product in an abnormal fashion means that theoretically there is at least one tumor-associated antigen (TAA) (it may be an autoantigen) available as a target. Secondly, we now know that any cellular protein (membrane, cytoplasmic or nuclear) may be presented as a peptide, in the context of major histocompatibility complex (MHC) molecules, for recognition by the T lymphocyte receptor complex. Thirdly, whilst it is clear that the immune response has failed the cancer patient, it is also true that it has not suffered irreversible meltdown, i. e. deletion of tumor-reactive T lymphocytes. Finally, it is now recognized that dendritic cells (DCs) are the key cellular elements for initiating and directing immune responses. As DC biology appears to be abnormal in cancer patients, the simplest hypothesis of the day is to use activated DCs to present relevant TAAs to the patient's immune system and thus generate an effective therapeutic response. This chapter will review the physiology of DC biology in the cancer patient, DC preparations and clinical trial results, whilst predicting areas requiring attention in order to optimize DC cancer vaccination for future patient benefit. DC PropertiesDCs originate from CD34 + hematopoietic stem cells, circulate in peripheral blood and are found in virtually all tissues of the body. In peripheral blood, DCs are a morphologically heterogeneous cell population, including DCs with membrane processes (ªmyeloid DCº) and DCs with plasmacytoid morphology (ªplasmacytoid monocytesº, ªplasmacytoid T lymphocyteº, ªlymphoid DCsº) [1,2]. In the skin, DCs are present as epidermal Langerhans cells (LCs) with their characteristic Birbeck ISBNs: 3-527-30441-X (Hardback);(Electronic) 3-527-60079-5 granules [3] and dermal DCs [4,5], which have a subtly different morphology and phenotype. In secondary lymphoid tissues they are present as interdigitating DCs with prominent membrane processes in the T cell area and as ªplasmacytoid monocytesº around high endothelial venules (HEVs) [6]. Monocytes may also differentiate directly into DC-like cells in sites of inflammation [7]. Whilst there is some uncertainty about the identity of the different DC populations and their differentiation, it is clear that a variety of growth factors and cytokines drive DC development [8]. Furthermore, chemokines direct their migration [9] and other soluble compounds influence their function.Blood DCs are commonly defined as lineage negative (Lin ± ), MHC class II positive (MHC-II + ) cells, lacking the CD14 (monocyte), CD3 (T cell), CD19 (B cell) and CD56 [natural killer (NK) cell] lineage markers, but expressing MHC class II molecules at high density, on their surface. They express various adhesion molecules including CD11 a ...

Conjugation of Latent Membrane Protein (LMP)-2 Epitope to Gold Nanoparticles as Highly Immunogenic Multiple Antigenic Peptides for Induction of Epstein−Barr Virus-Specific Cytotoxic T-Lymphocyte Responses in Vitro

“…Dendritic cells (DC) are professional antigen-presenting cells for activation of antigen-specific CTL, which underlies effective cancer immunotherapy. Dendritic cells are responsible for processing and presenting human leukocyte antigen (HLA)-restricted peptide epitopes to CD8+ T cells through the major histocompatibility complex (MHC)-I pathway − . Recently, one of us reported that intranodal injection of dendritic cells ex vivo pulsed with a HLA-A11 restricted LMP-2 epitope (SSCSSCPLSK) induced EBV specific CTL in vivo, and regression of metastatic tumor in selected NPC patients has been observed .…”