Regulation of tumor immunity by tumor/dendritic cell fusions

Abstract

The goal of cancer vaccines is to induce antitumor immunity that ultimately will reduce tumor burden in tumor environment. Several strategies involving dendritic cells- (DCs)- based vaccine incorporating different tumor-associated antigens to induce antitumor immune responses against tumors have been tested in clinical trials worldwide. Although DCs-based vaccine such as fusions of whole tumor cells and DCs has been proven to be clinically safe and is efficient to enhance antitumor immune responses for inducing effective immune response and for breaking T-cell tolerance to tumor-associated antigens (TAAs), only a limited success has occurred in clinical trials. This paper reviews tumor immune escape and current strategies employed in the field of tumor/DC fusions vaccine aimed at enhancing activation of TAAs-specific cytotoxic T cells in tumor microenvironment.

Figure 1

The role of helper T cells in tumor immunity. CD4+ T-helper cells play extensive roles and are able to interact with the tumor cell and immune effectors. Th1 cells secrete type I cytokines such as interleukin 2 (IL-2) and IFN-γ, resulting in the activation of DCs, which can stimulate CTLs. Tumor-specific Th1 cells regulate the survival and persistence of CD8+ effector T cells as memory cells. Th2 cells secrete type II cytokines, such as IL-4 and IL-10. Th2 cells can enhance the generation of humoral, antibody-based antitumor responses. Th17 cells secrete IL-17 elicit tissue inflammation implicated in autoimmunity. Inducible CD4+ regulatory T cells (iTreg) exhibit a strong immunosuppressive activity for antitumor immunity.

Figure 2

Characterization of tumor/DC fusions. Tumor/DC fusions express MHC class I, II, costimulatory molecules and tumor-associated antigens (TAAs). The fusions are able to process tumor-derived peptides and MHC class I peptides derived from DCs. They form MHC class I-peptide complexes, in the endoplasmic reticulum, which are transported to the cell surface and presented to CD8+ T cells. Similarly, the fusions can synthesize MHC class II peptides derived from DC in the endoplasmic reticulum, which are transported to the cytoplasm where MHC class II-peptide complexes are assembled with tumor-derived peptides and presented to CD4+ T cells.

Figure 3

Immunosuppression in tumor microenvironment. Tumors secrete various factors such as VEGF, IL-6, IL-10, TGF- β, Fas-L, and IDO, all of which promote the accumulation of heterogeneous populations of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), or immature DCs. These immunosuppressive cells inhibit antitumor immunity by various mechanisms, including depletion of arginine and elaboration of reactive oxygen species (ROS) and nitrogen oxide (NO). The tumor microenvironment also promotes the accumulation of regulatory T cells (Tregs) that suppress CD8+ CTL function through secretion of IL-10 or TGF-β from Tregs and tumors.

Figure 4

Activation or inactivation of T cells by tumor/DC fusions. After acquired antigens in the periphery, tumor/DC fusions migrate to the draining lymph nodes, where they encounter a cognate CD4+ or CD8+ T cells. The mature tumor/DC fusions produce stimulatory factors, such as IL-12 and heat-shock proteins (HSPs), while the immature fusions produce suppressive factors (TGF- β, IL-10, or IDO, etc.). High expression of costimulatory and MHC class I and II molecules by mature fusions is essential to promote survival and proliferative capacity of the activated CD8+ CTLs. Mature fusions induce efficient CD8+ T-cell activation with high production of perforin and granzyme B. On the other hand, immature fusions may induce, at least in part, Tregs. In tumor microenvironment, the consequence of products from tumor cells enhances local suppressive immunity.