Dendritic cell vaccines for brain tumors

Abstract

Over the past decade, dendritic cell-based immunotherapy for central nervous system tumors has progressed from preclinical rodent models and safety assessments to phase I/II clinical trials in over 200 patients, which have produced measurable immunologic responses and some prolonged survival rates. Many questions regarding the methods and molecular mechanisms behind this new treatment option, however, remain unanswered. Results from currently ongoing and future studies will help to elucidate which dendritic cell preparations, treatment protocols, and adjuvant therapeutic regimens will optimize the efficacy of dendritic cell vaccination. As clinical studies continue to report results on dendritic cell-mediated immunotherapy, it will be critical to continue refining treatment methods and developing new ways to augment this promising form of glioma treatment.

Figure 1

Schematic of dendritic cell antigen processing and presentation via distinct MHC-I and MHC-II targeted pathways. Foreign antigens are sampled from the environment via dendritic cell phagocytosis or pinocytosis. Once vacuolized, antigen-containing vesicles are directed down one of two MHC pathways that result in cell surface presentation. A) Antigen containing vesicle encounters endoplastmic reticulum-phagosome. Antigen is retro-translocated into the cytoplasm via Sec 61 where proteosome complexes mediate peptide degradation. The resultant epitopes are translocated back into the ER-phagosome via the transporter-associated protein (TAP), where they are loaded onto MHC-I complexes and extruded for membrane integration and antigen presentation on the cell surface. B) Antigen-containing vesicle encounters lysosome which cleaves peptides using acid proteases. MHC-II complexes formed within the ER and subsequently processed and extruded from the Golgi apparatus are transported to peptide containing endosomes for antigen loading.

Figure 2

Diagram depicting the multiple dendritic cell-lymphocyte interactions that take place in the immune cascade following antigen processing and presentation by DCs. Dendritic cell activation of NK T cells through self ligands (not shown) and IL-12 results in IFN-γ release and subsequent activation of CD4+ and CD8+ T cells. CD4 and CD8 T cell receptors (TCR) interact with peptide-MHC II and I complexes, respectively. CD40L-CD40 interactions between CD4+ T cells and a DC and CD28-B7 interactions between CD8+ T cells and a DC are critical costimulatory interactions that must occur for appropriate T-cell signaling and immune responsiveness.