Monocyte-derived dendritic cells in cancer immunotherapy : Considerations on their applicability

Abstract

Cancer is the leading cause of death in the developed world. While treatment options and detection have improved over the last century, mortality rate remains high especially in metastatic disease. Traditional treatment for metastatic cancer is often life prolonging with limited curative intentions. Furthermore, many traditional treatment regimes such as chemotherapy and radiotherapy have considerable side effects that drastically reduce quality of life. Prostate cancer is the second most common cancer in men worldwide and has limited treatment options with curative intention. The introduction of checkpoint-inhibitors in treatment of melanoma showed that immune-response against cancer is possible, and that patients who respond have long survival.

Dendritic cell-based immunotherapy has shown to work in animal models and is a promising method to stimulate an immune response against cancer. One of the easiest methods to obtain dendritic cells (DC) is by generation from monocytes. These monocyte-derived DC (moDC) can be loaded with antigens and used to stimulate immune responses. However, recent clinical trials using moDC for immunotherapy showed disappointing results.

The overall goal of this thesis was to investigate factors that affect the properties of moDC such as culture conditions and maturation stimuli and how that affects their interaction with T-cells.

In paper I the effect of OK432 as a maturation stimulus for moDC was investigated in various formats. Properties such as phenotype, cytokine profile, migratory capacity and T-cell stimulatory capacity was measured. The addition of PGE2 resolved the lack of migratory capacity in OK432 matured moDC. It was concluded that OK432 together with CL097 and PGE2 is a promising cocktail for moDC maturation in immunotherapy.

In paper II the effects of the culture dish surface on the generation of moDC was investigated. Properties such as phenotype and cytokine profile was measured. Overall, the surface adhesion properties of cell culture dishes used significantly affected many properties of moDC in both immunogenic and tolerogenic culture conditions.

In paper III, moDC from patients with metastatic prostate cancer were investigated to determine if patient cells were capable of responding to maturation stimuli such as the OK432 cocktail developed in paper I. MoDC from patients showed a mature phenotype and were able to stimulate autologous T-cells in an antigen-specific manner.