Engineering dendritic cell vaccines to improve cancer immunotherapy

Abstract

At the interface between the innate and adaptive immune system, dendritic cells (DCs) play key roles in tumour immunity and hold a hitherto unrealized potential for cancer immunotherapy. Here we review the role of distinct DC subsets in the tumour microenvironment, with special emphasis on conventional type 1 DCs. Integrating new knowledge of DC biology and advancements in cell engineering, we provide a blueprint for the rational design of optimized DC vaccines for personalized cancer medicine.

Fig. 1

Genetic approaches for improving dendritic cell-based vaccines. RNA interference (RNAi), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), or viral transduction may be used to modulate expression of different targets and modulate various pathways of anti-tumour immunity. Solid arrows indicate direct genetic targets, while dashed arrows indicate downstream effects. (i) Enhancing tumour-associated antigen (TAA) presentation: expression of an engineered receptor (e.g., extracellular vesicle-internalizing receptor, EVIR) promotes in situ antigen uptake and increases presentation of relevant TAAs; silencing of YTHDF1 reduces translation of lysosomal cathepsins, decreasing antigen degradation after internalization and improving cross-presentation capacity. (ii) Enhancing lymph node migration: direct overexpression of CCR7 improves lymph node migration^,; alternatively, overexpression of miR-155 upregulates CCR7 and IL-12 secretion^,,. (iii) Abating immunosuppression: silencing dendritic cell (DC)-intrinsic immunosuppressive molecules, such as PD-L1, improves T cell activation capacity; upregulation of IL-12, IFN-γ, or CXCL9 improves immune checkpoint blockade^,,, which can be achieved via direct overexpression of these signals^,, via activation of TLR3 and TLR8, which induces IL-12 and IFN-γ release^,,, or via CD40 agonism through transgenic expression of CD40L that activates IL-12 release^,,,. (iv) Enhancing immune cell recruitment: upregulation of different chemokines at the tumour site drives recruitment of various immune cells, including CXCL9-driven recruitment of CXCR3⁺ T cells and natural killer (NK) cells^,, CCL21-driven recruitment of CCR7⁺ DCs and T cells^,, and XCL1-driven recruitment of XCR1⁺ cDC1s.

Fig. 2

Proposed manufacturing procedures for improving dendritic cell-based vaccines. Black arrows indicate conventional manufacturing steps, while red arrows indicate proposed modifications or additions. CD14⁺ monocytes or CD34⁺ haematopoetic stem and progenitor cells (HSPCs) are isolated from leukapheresis products, differentiated into immature monocyte-derived dendritic cells (MoDCs) with IL-4 and GM-CSF. Alternatively, adult dermal fibroblasts are directly reprogrammed to conventional type 1 DCs (cDC1s) by lentiviral vector (LV) transduction of transcription factors without the need for leukapheresis, or CD34⁺ HSPCs differentiated under FLT3L and Notch signalling to produce cDC1s at high yields^,. The resulting DCs are then loaded with tumour-associated antigens (TAAs) of various forms and matured with toll like receptor (TLR) ligands or inflammatory cytokines. At this step, DCs could be genetically engineered to improve their anti-tumoural functions (see Fig. 1). Mature, TAA-loaded DCs are then re-infused to the patient, which could be combined with immunomodulatory drugs such as immune checkpoint blockade.