Cancer immunotherapy via dendritic cells

Abstract

Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.

Figure 1. Launching the immune response

Antigens can reach lymph nodes through two pathways: via lymphatics, where the antigen is captured by lymph node-resident dendritic cells (DCs), or via tissue-resident DCs. These immature DCs capture antigens, and DC activation triggers their migration towards secondary lymphoid organs and their maturation. DCs display antigens in the context of classical major histocompatibility (MHC) class I and MHC class II molecules or in the context of non-classical CD1 molecules, which allow the selection of rare antigen-specific T lymphocytes. Activated T cells drive DCs towards their terminal maturation, which induces further expansion and differentiation of T lymphocytes into effector T cells. If DCs do not receive maturation signals, they will remain immature and antigen presentation will lead to immune regulation and/or suppression. T_Reg cell, regulatory T cell.

Figure 2. DC maturation

Dendritic cell (DC) maturation is a simple concept that is rendered complex by the likelihood that not all mature (or activated) DCs are equivalently immunogenic. For example, under steady state conditions, particularly in lymphoid tissue, DC populations that display at least some of the features of mature DCs (for example, elevated expression of surface co-stimulatory molecules) can be found despite the absence of overt inflammation or infection. The functional importance of these cells is unknown but it is not unreasonable to suspect that tolerogenic DCs may have to acquire the capacity to present antigen, migrate and interact with T cells (characteristics of mature DCs) in order to induce antigen-specific regulatory T (T_Reg) cells or to induce anergy or T cell apoptosis at high efficiency. The priming of T_Reg cells either in the thymus or in the periphery may require activation by endogenous mediators, such as thymic stromal lymphopoietin (TSLP) or WNT, respectively^,. Whether these mediators induce morphologically recognizable maturation in vivo is likely but not known. However, it is clear that resting or immature DCs can or must be activated in some way to induce T cell tolerance; thus, it is inaccurate to assume that the relevant steady state DCs are ‘immature’ or resting. IL, interleukin; T_H, T helper.

Figure 3. Subsets of DCs

The two arms of the adaptive immune response — humoral and cellular — are regulated by different subsets of dendritic cells (DCs) in humans. Humoral immunity is preferentially regulated by CD14⁺ dermal DCs, which produce interleukin-12 (IL-12). IL-12, in turn, acts directly on B cells and promotes the development of T follicular helper (T_FH) cells. Cellular immune responses in the skin are preferentially regulated by Langerhans cells. Among the candidate mediators is IL-15. It is also possible that Langerhans cells can preferentially activate a dedicated subset of CD4⁺ T cells that are specialized to help CD8⁺ cytotoxic T lymphocytes (CTLs). Given their capacity to cross-present antigens to CD8⁺ T cells, CD141⁺ DCs might be involved in the development of CTL-mediated responses. CD141⁺ DCs might also be involved in the development of humoral responses through IL-12 secretion. PC, plasma cell.

Figure 4. DC interaction with tumour cells: antigen capture

The figure illustrates some phagocyte surface receptors and their putative ligands that are implicated in the recognition of dying tumour cells. Receptors shown in blue represent molecules expressed by dying tumour cells, receptors shown in orange represent molecules expressed by dendritic cells (DCs) and the receptors shown in green function as a ‘bridge’ between the two cells. BAI1, brain-specific angiogenesis inhibitor 1; C1Q, complement C1q subcomponent; C3β, complement C3β; CRP, cysteine-rich protein; GAS6, growth arrest-specific protein 6; HMGB1, high mobility group protein B1; HSP, heat shock protein; LDL, low-density lipoprotein; LOX1, lectin-like oxidized LDL receptor 1; LPC, lipid lysophosphatidylcholine; MBL, mannose binding lectin; MFG-E8, milk fat globule-EGF factor 8 (also known as lactadherin); P2Y2, P2Y purinoceptor 2; PS, phosphatidylserine; S1P, sphingosine 1-phosphate; SAP, sphingolipid activator protein 1; SIRPα, signal-regulatory protein-α; STAB2, stabilin 2; TIM4, T cell membrane protein 4; TLR4, Toll-like receptor 4; TSP, thrombospondin.

Figure 5. The interaction of DCs with tumour cells: modulation of DC maturation

Cancer cells attract immature dendritic cells (DCs), possibly through chemokines such as CCL20 or CXCL12. DCs can then be exposed to cancer-derived factors — for example, thymic stromal lymphopoietin (TSLP) — which skews their maturation towards T helper 2 (T_H2)-type inflammation. In this environment, T_H2 cells promote tumour development either directly or via macrophages. EGF, epidermal growth factor; IL-13, interleukin-13; OX40L, OX40 ligand.

Figure 6. DCs and cancer immunotherapy

a | Random targeting of dendritic cells (DCs) in ‘endogenous’ vaccination results from in vivo antigen release owing to immunogenic cell death in response to chemotherapy, radiotherapy and immunomodulation approaches that are targeted at T cells. b | Vaccines can be based on ex vivo-generated tumour antigen-loaded DCs that are injected back into patients. c | Specific in vivo DC targeting with DC antibodies fused with antigens and with DC activators is shown. d | Targeting DCs in the tumour microenvironment to reprogramme pro-tumour inflammation towards tumour rejection is shown. MHC, major histocompatibility complex; TLR, Toll-like receptor.