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Review
. 2018 Oct 1:9:2265.
doi: 10.3389/fimmu.2018.02265. eCollection 2018.

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time

Wouter W van Willigen  1   2 , Martine Bloemendal  1   2 , Winald R Gerritsen  1 , Gerty Schreibelt  2 , I Jolanda M de Vries  2 , Kalijn F Bol  1   2
Affiliations
Review

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time

Wouter W van Willigen et al. Front Immunol. .

Abstract

Immune checkpoint inhibitors propelled the field of oncology with clinical responses in many different tumor types. Superior overall survival over chemotherapy has been reported in various metastatic cancers. Furthermore, prolonged disease-free and overall survival have been reported in the adjuvant treatment of stage III melanoma. Unfortunately, a substantial portion of patients do not obtain a durable response. Therefore, additional strategies for the treatment of cancer are still warranted. One of the numerous options is dendritic cell vaccination, which employs the central role of dendritic cells in activating the innate and adaptive immune system. Over the years, dendritic cell vaccination was shown to be able to induce an immunologic response, to increase the number of tumor infiltrating lymphocytes and to provide overall survival benefit for at least a selection of patients in phase II studies. However, with the success of immune checkpoint inhibition in several malignancies and considering the plethora of other treatment modalities being developed, it is of utmost importance to delineate the position of dendritic cell therapy in the treatment landscape of cancer. In this review, we address some key questions regarding the integration of dendritic cell vaccination in future cancer treatment paradigms.

Keywords: adjuvant; cancer; checkpoint inhibitor; dendritic cell; immunotherapy; vaccination.

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Figures

Figure 1
Figure 1
The induction of a tumor-specific immune response by dendritic cell vaccination. Tumor antigen-specific T-cells are activated by dendritic cells, which are ex vivo loaded with tumor antigen(s). Activated T-cells subsequently patrol the body in search of their respective antigen. When their target is found, T-cells exert their cytotoxic functions on cancer cells. CD8, cluster of differentiation 8 (cytotoxic T-cell); DC, dendritic cell; MHC, major histocompatibility complex.
Figure 2
Figure 2
The process of generating dendritic cell vaccines. Autologous dendritic cells or monocytes are obtained via an apheresis procedure. Monocytes first have to be differentiated into dendritic cells. Subsequently, dendritic cells are matured and loaded with tumor antigen. Finally, the dendritic cells are administrated to the patient. DC, dendritic cell.
Figure 3
Figure 3
The difference in tumor load-associated immune suppression between minimal residual disease and a situation with high tumor load. Antigen-specific T-cells induced by dendritic cell vaccination eliminating minimal residual disease after surgical resection of cancer (A). Minimal residual disease is associated with less immune suppression as opposed to a situation with more tumor load (B). Tumor load-associated immune suppression is caused by (among other factors) regulatory T-cells, myeloid derived suppressor cells, soluble immune suppressive factors (such as IL-10, TGFβ and VEGF) and indoleamine 2,3-dioxygenase activity. Vaccination-induced T-cells can be rendered anergic by this immune suppression, resulting in inferior clinical results. Therefore, dendritic cell vaccination might be more effective in the adjuvant setting. IDO, indoleamine 2,3-dioxygenase; MDSC, myeloid derived suppressor cells; Treg, regulatory T-cells.
Figure 4
Figure 4
Combinational strategies to achieve synergy between several treatment modalities and dendritic cell vaccination. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; mAb, monoclonal antibody; CD8, cluster of differentiation number 8 (cytotoxic T-cell); MDSC, myeloid derived suppressor cells; PD-1, programmed cell death protein; PD-L1, programmed death-ligand 1; Treg, regulatory T-cells.
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