Dendritic cells: are they clinically relevant?

Abstract

Cancer vaccines have undergone a renaissance because of recent clinical trials showing promising immunologic data and some clinical benefit to patients. Current trials exploiting dendritic cells (DCs) as vaccines have shown durable tumor regressions in a fraction of patients. Clinical efficacy of current vaccines is hampered by myeloid-derived suppressor cells, inflammatory type 2 T cells, and regulatory T cells, all of which prevent the generation of effector cells. To improve the clinical efficacy of DC vaccines, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome regulatory T cells and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the DC system, including the existence of distinct DC subsets. Critical to the design of better vaccines is the concept of distinct DC subsets and distinct DC activation pathways, all contributing to the generation of unique adaptive immune responses. Such novel DC vaccines will be used as monotherapy in patients with resected disease and in combination with antibodies and/or drugs targeting suppressor pathways and modulation of the tumor environment in patients with metastatic disease.

Figure 1. Dendritic cells

DCs reside in the tissue where they are poised to capture antigens (109). During inflammation, circulating precursor DC enter tissues as immature DC (109). DCs can encounter pathogens (e.g.: viruses) directly, which induce secretion of cytokines (e.g.: IFN-□); or indirectly through the pathogen effect on stromal cells. Cytokines secreted by DCs in turn activate effector cells of innate immunity such as eosinophils, macrophages and NK cells. Microbe activation triggers DCs migration towards secondary lymphoid organs and simultaneous activation (maturation). These activated migratory DCs that enter lymphoid organs display antigens in the context of classical MHC class I and class II or non-classical CD1 molecules, which allow selection of rare circulating antigen-specific T lymphocytes. Activated T cells help drive DCs toward their terminal maturation, which allows lymphocyte expansion and differentiation. Activated T lymphocytes traverse inflamed epithelia and reach the injured tissue, where they eliminate microbes and/or microbe-infected cells. B cells, activated by DCs and T cells, migrate into various areas where they mature into plasma cells that produce antibodies that neutralize the initial pathogen. Antigen can also reach draining lymph nodes without involvement of peripheral tissue DCs and be captured and presented by lymph node resident DCs (110). The quality of antibody responses is determined by intDCs while the quality of CTL responses is dictated by LCs.

Figure 2. Loading antigen on ex vivo DC vaccines

A number of ways by which the antigen can be delivered to DCs have been identified. The advantages and disadvantages are discussed. Currently, we are developing the strategy to load DCs with long peptides representing defined tumor antigens and providing both CD8⁺ and CD4⁺ T cell epitopes.

Figure 3. DC vaccines in combination therapies

Current active immunotherapy trials have shown durable tumor regressions in a fraction of patients. However, clinical efficacy of current approaches is limited, possibly because tumors invade the immune system by means of myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs). To improve the clinical efficacy of immunotherapies, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of an immunosuppressive tumor microenvironment. This can be achieved by developing combination therapies targeting these three major components.

Figure 4. Approaches to DC-based immune intervention in cancer

1) Vaccines based on antigen with or without adjuvant that target DCs randomly. That might result in vaccine antigens being taken up by a “wrong” type of DCs in the periphery which might lead to “unwanted” type of immune response. Vaccine antigens could also flow to draining lymph nodes where they can be captured by resident DCs; 2) Vaccines based on ex-vivo generated tumor antigen-loaded DCs that are injected back into patients; and 3) specific in vivo DC targeting with anti-DC antibodies fused with antigens and with DC activators. 4) Next generation clinical trials will test optimized DC vaccines combined with patient-adjusted approaches to block Tregs and to breakdown the tumor environment. These therapies will be tested in pre-selected patients thereby leading to personalized therapy.