Abstract
Therapeutic dendritic cell (DC) cancer vaccines rely on the immune system to eradicate tumour cells. Although tumour antigen-specific T cell responses have been observed in most studies, clinical responses are fairly low, arguing for the need to improve the design of DC-based vaccines. The incorporation of small interfering RNAs (siRNAs) against immunosuppressive factors in the manufacturing process of DCs can turn the vaccine into potent immune stimulators. Additionally, siRNA modification of ex vivo-expanded T cells for adoptive immunotherapy enhanced their killing potency. Most of the siRNA-targeted immune inhibitory factors have been successful in that their blockade produced the strongest cytotoxic T cell responses in preclinical and clinical studies. Cancer patients treated with the siRNA-modified DC vaccines showed promising clinical benefits providing a strong rationale for further development of these immunogenic vaccine formulations. This review covers the progress in combining siRNAs with DC vaccines or T cell therapy to boost anti-tumour immunity.
Highlights
Dendritic cells (DCs) are specialized antigen presenting cells (APCs) derived from bone marrow precursors and are abundant at the skin and internal and mucosal surfaces, where they sense and sample the environment for self- and non-self antigens [1]
While plasmacytoid DCs are well equipped to produce type- I-inteferons in response to infections, CD141+ DC and Langerhans cells are efficient in cross-presentation of cellular antigens and can prime naïve CD8+ T cells to differentiate into effector cytotoxic T lymphocytes (CTLs) [1]
What was remarkable was the objective clinical responses obtained with either IDO- or suppressor of cytokine signalling (SOCS)-1-silenced DC vaccine
Summary
Dendritic cells (DCs) are specialized antigen presenting cells (APCs) derived from bone marrow precursors and are abundant at the skin and internal and mucosal surfaces, where they sense and sample the environment for self- and non-self antigens [1]. Depending on the nature and time of activation, DCs can express co-inhibitory molecules such as programmed cell death ligand 1 (PD-L1). The binding of lymphocyte activation gene 3 (LAG3) protein on protein on Treg cells to MHC II molecules on immature DCs activates an inhibitor signaling pathway. Treg cells to MHC II molecules on immature DCs activates an inhibitor signaling pathway that suppress that suppress DC maturation. This cross-talk between Tregs and DCs is important for the DC maturation. Given the role played by DCs and T cells in tumour vaccines and ACT should include inhibitors against immune suppressive cytokines, checkpoint immunity, the current engineering strategies for DC cancer vaccines and ACT should include inhibitors ligands, and other suppressive factors such as IDO and ARG-1. Overview on the therapeutic potential of cancer vaccination that do not relay on ex vivo DCs
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