Dendritic cells: a critical player in cancer therapy?

Abstract

Cancer immunotherapy seeks to mobilize a patient's immune system for therapeutic benefit. It can be passive, that is, transfer of immune effector cells (T cells) or proteins (antibodies), or active, that is, vaccination. Early clinical trials testing vaccination with ex vivo generated dendritic cells (DCs) pulsed with tumor antigens provide a proof-of-principle that therapeutic immunity can be elicited. Yet, the clinical benefit measured by regression of established tumors in patients with stage IV cancer has been observed in a fraction of patients only. The next generation of DC vaccines is expected to generate large numbers of high avidity effector CD8 T cells and to overcome regulatory T cells and suppressive environment established by tumors, a major obstacle in metastatic disease. Therapeutic vaccination protocols will combine improved DC vaccines with chemotherapy to exploit immunogenic chemotherapy regimens. We foresee adjuvant vaccination in patients with resected tumors but at high risk of relapse to be based on in vivo targeting of DCs with fusion proteins containing anti-DCs antibodies, antigens from tumor stem/propagating cells, and DC activators.

Figure 1. Subsets of human dendritic cells

Blood DCs, mobilized by FLT3 ligand, contain both CD11c⁺ myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). mDCs can be generated by culturing CD34⁺ HPCs with GM-CSF and TNF. In this way, two DC subsets can be obtained: Langerhans cells (LCs) that are specialized in the induction of cellular immunity including generation of cytotoxic T cells, and interstitial DCs that are specialized in launching humoral immunity and antibody response. Most studies of DCs so far have been carried out with DCs made by culturing monocytes with GM-CSF and IL-4, a simple procedure that yields a homogenous population of DCs. These preparations contain cells that resemble interstitial DCs and are devoid of LCs due to transcriptional regulation of Langerin expression by IL-4. These DCs are immature and require exogenous factors for maturation. Replacement of IL-4 with other cytokines leads to generation of a “Rainbow” of mDCs whose composition and function is determined by cytokine to which monocytes are exposed. Thus, in combination with GM-CSF, thymic stroma lymphopoietin (TSLP) generates mDCs promoting type 2 immunity while TNF and IL-15 generate mDCs containing LCs. The role of pDCs in vaccination against cancer remains to be determined. However, in the human these cells are likely to be the target of CpG since they uniquely express TLR9. Their capacity to rapidly secrete high amounts of type I IFN might contribute to anti-tumor activity of CpG.

Figure 2. Current obstacles to clinically effective DC vaccination protocols and strategy to overcome them

First generation DC vaccines: Early clinical trials with first generation DC vaccines (left panel) showed the induction of immune responses to vaccine antigens. However, the clinical responses are still infrequent. Possible contributing factors can be grouped into: i) vaccine features, and ii) suppressive pathways established by tumors. Vaccine features include: i) insufficient CD4⁺ T cell help; ii) generation of low affinity CTLs; and iii) generation of T regs. Suppressive pathways involve: i) suppressor cells, both T regs as well as myeloid suppressor cells; ii) suppressor molecules expressed by tumors such as PD-L1; and iii) suppressive factors secreted by tumors, for example TGF-β or VEGF. Suppression can act at the level of the induction of immune response and at the effector function level including inhibiting the release of cytotoxic effector molecules Granzyme B and perforin. Second generation DC vaccines: Improved next generation DC vaccines will harness Langerhans cells and microbial activation signals leading to: i) secretion of high amounts of cytokines such as IL-12, which will generate strong Th1 response and helper function for generation of memory T cells; and IL-15 which will help generation of high avidity CTLs that might be resistant to tumor microenvironment; and ii) strong costimulation mediated via at least three molecular pathways such as CD80, CD70 and 4-1BB. This in combination with therapies that will permit to eliminate T regs and block tumor microenvironment will results in the full activity of elicited CTLs and tumor rejection.