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. Immunosuppressive Mechanisms of the TME and Tumor Cells that Hamper the Efficacy of DC Therapy Both tumor cells and immunosuppressive immune cells in the TME hamper the effectivity of DC therapy through various mechanisms, such as the expression of inhibitory molecules, secretion of inhibitory cytokines or enzymes, induction of tolerogenic cell death, and creation of a dense extracellular matrix. 18,19 Tumor cells recruit immunosuppressive immune cells, fibroblasts, 20 and endothelial cells to the TME through the secretion of growth factors, chemokines, and cytokines, thereby hampering the infiltration of DCs and other pro-inflammatory cells into the TME. 21,22 Moreover, fibroblasts and immunosuppresive immune cells interact synergistically with each other to maximize the immunosuppressive character of the TME.

Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

“…The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dentritic cell (DC)-based immunotherapy [1][2][3][4][5][6][7]. DCs are Pharmaceutics 2020, 12, 210 2 of 10 essential in immunity due to their role in priming, activating, and directing the T cells to target tumor cells and, thereby, by promoting antitumorigenic responses [1,8,9].…”

Conjugation of TLR7 Agonist Combined with Demethylation Treatment Improves Whole-Cell Tumor Vaccine Potency in Acute Myeloid Leukemia

“…While the efficacy and immunogenicity of the DC vaccines have been demonstrated by numerous clinical studies, the results have been largely misleading. This can be due in part to functional deficiencies in cells comprising traditional vaccine formulations, which are poorly prepared to resolve the immunosuppressive tumor microenvironment restricting DC and cell activity [15,32]. Our new vaccine made by conjugating the TLR7 agonist SZU-106 to DAC treated AML cells were aimed to target all three key components in the classical immune response.…”

Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update

“…The combination of cancer vaccines (including DC vaccines) with chemotherapy has also been explored in the clinic (for a review also of ongoing trials see [129][130][131][132]). While significant synergism seems apparent only in few trials, most of them DC studies [133][134][135][136], a negative impact has never been reported, as the rules for a successful combination-also derived from animal studies-have been taken into account.…”