Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC.

Robert Dalton,Elena Kostenko,Kenneth L Wright,Michelle Maurin,Thu Le Trinh,Grace Ward,Alexandra Calescibetta,Jun Min Zhou,Erika A Eksioglu,Pingyan Cheng,Sheng Wei,Nhan Tu,Danielle Gilvary,Xianghong Chen

doi:10.3390/ijms22031241

Robert Dalton, Elena Kostenko + Show 12 more

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https://doi.org/10.3390/ijms22031241

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Abstract

Dendritic cells (DCs) are professional antigen presenting cells with a great capacity for cross-presentation of exogenous antigens from which robust anti-tumor immune responses ensue. However, this function is not always available and requires DCs to first be primed to induce their maturation. In particular, in the field of DC vaccine design, currently available methodologies have been limited in eliciting a sustained anti-tumor immune response. Mechanistically, part of the maturation response is influenced by the presence of stimulatory receptors relying on ITAM-containing activating adaptor molecules like DAP12, that modulates their function. We hypothesize that activating DAP12 in DC could force their maturation and enhance their potential anti-tumor activity for therapeutic intervention. For this purpose, we developed constitutively active DAP12 mutants that can promote activation of monocyte-derived DC. Here we demonstrate its ability to induce the maturation and activation of monocyte-derived DCs which enhances migration, and T cell stimulation in vitro using primary human cells. Moreover, constitutively active DAP12 stimulates a strong immune response in a murine melanoma model leading to a reduction of tumor burden. This provides proof-of-concept for investigating the pre-activation of antigen presenting cells to enhance the effectiveness of anti-tumor immunotherapies.

Highlights

Dendritic cells (DCs) mediate the critical interface between innate and adaptive immunity to both microbes and neoplasia [1]
We demonstrate here the beneficial anti-tumor immune responses in an in vivo murine tumor model treated with constitutively active DAP12 expressing monocyte-derived DCs (Mo-DCs)
Given the fact that Ad-P19 and Ad-P23 up-regulate CCR7 expression on human monocyte-derived DCs (MoDCs), which is associated with enhanced migration toward MIP-3β (CCL19) in vivo [27], and increase the secretion of IL-8 which is linked to migration [26], we examined whether Ad-P19 or Ad-P23 transduced human Mo-DC could migrate toward CCL19 in a chemotaxis trans-well assay

Summary

Introduction

Dendritic cells (DCs) mediate the critical interface between innate and adaptive immunity to both microbes and neoplasia [1] These professional antigen presenting cells (APC) possess the unique capacity to cross-present exogenous antigens derived from tumors to generate both primary and secondary anti-tumor cytolytic responses. Immature cells, from which most DC vaccine therapies are derived, are not migratory or anti-tumoral preventing the migration of tumor-specific cells to the tumor site and elicitation of an effective response [3] This is partly due to the reduced upregulation or incomplete activation of stimulatory receptors critical for proper DC activation [4]. Many of these stimulatory receptors (such as TREM, Siglec-H, and SIRP-β) associate with Immune-receptor tyrosine-based activation motif (ITAM)-containing adapter molecules through their negatively charged residues in the transmembrane domain to transduce their pro-inflammatory signals to the nucleus [5,6,7]

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