Enhancing Dendritic Cell Therapy in Solid Tumors with Immunomodulating Conventional Treatment

Abstract

Dendritic cells (DCs) are the most potent antigen-presenting cells and are the key initiator of tumor-specific immune responses. These characteristics are exploited by DC therapy, where DCs are ex vivo loaded with tumor-associated antigens (TAAs) and used to induce tumor-specific immune responses. Unfortunately, clinical responses remain limited to a proportion of the patients. Tumor characteristics and the immunosuppressive tumor microenvironment (TME) of the tumor are likely hampering efficacy of DC therapy. Therefore, reducing the immunosuppressive TME by combining DC therapy with other treatments could be a promising strategy. Initially, conventional cancer therapies, such as chemotherapy and radiotherapy, were thought to specifically target cancerous cells. Recent insights indicate that these therapies additionally augment tumor immunity by targeting immunosuppressive cell subsets in the TME, inducing immunogenic cell death (ICD), or blocking inhibitory molecules. Therefore, combining DC therapy with registered therapies such as chemotherapy, radiotherapy, or checkpoint inhibitors could be a promising treatment strategy to improve the efficacy of DC therapy. In this review, we evaluate various clinical applicable combination strategies to improve the efficacy of DC therapy.

Keywords: checkpoint inhibitors; chemotherapy; dendritic cell-based therapy; immunogenic cell death; immunotherapy; macrophages; myeloid-derived suppressor cells; radiotherapy; regulatory T cells; tumor microenvironment.

Figure 1

Targeting the TME with Conventional Treatment Modalities (A) Inhibitory molecules (PD-(L)1, CTLA-4) inhibit T-cell effector, dendritic cell and natural killer (NK)-cell function, and T-cell activation in the lymphnode. Checkpoint inhibitors targeting (PD-(L)1, CTLA-4) can reinvigorate the anti-tumor immune response induced by dendritic cell (DC) therapy by blocking PD-(L)1 signaling in the tumor and CTLA-4 in the lymph node. (B) Regulatory T cells (Tregs) exert their immunosuppressive mechanisms through inhibitory molecules (CTLA-4), secretion of immunosuppressive cytokines (interleukin [IL]-10, TGFβ), and IL-2 consumption, thereby inhibiting NK-cells, T cells, and DCs and skewing tumor-associated macrophages (TAMs) in a unfavorable M2 phenotype. Tregs can be depleted with several chemotherapeutics (cyclophosphamide, paclitaxel, docetaxel, gemcitabine, temozolamide, and oxaliplatin). (C) Myeloid-derived suppressor cells (MDSCs) can exert their immunosuppressive function by relieving Arginase 1 (Arg1) and inducible nitric oxide synthase (iNOS) to deprive T cells of metabolites. MDSCs can be depleted by chemotherapeutics gemcitabine, 5-FU, cisplatin, and docetaxel and skewed into a M1 phenotype by docetaxel. (D) M2 TAMs secrete IL-10 and transforming growth factor β (TGF-β) and are involved in tissue remodeling, wound healing, and tumor progression. M2 TAMs can be depleted by CSF-1R and skewed into an M1 phenotype by CD40 agonists. (E) Immunogenic cell death (ICD) is characterized by secretion of ATP and high mobility group box 1 (HGMB-1) and expression of Calreticulin (CRT) on the cell surface, which stimulates DC phagocytosis, antigen presentation, and migration. ICD can be induced by chemotherapeutics, cyclophosphamide, oxaliplatin, paclitaxel, docetaxel and anthracyclines, and radiotherapy.