Adenovirus-engineered human dendritic cells induce natural killer cell chemotaxis via CXCL8/IL-8 and CXCL10/IP-10

Abstract

Recombinant adenovirus-engineered dendritic cells (Ad.DC) are potent vaccines for induction of anti-viral and anti-cancer T cell immunity. The effectiveness of Ad.DC vaccines may depend on the newly described ability of Ad.DC to crosstalk with natural killer (NK) cells via cell-to-cell contact, and to mediate activation, polarization and bridging of innate and adaptive immunity. For this interaction to occur in vivo, Ad.DC must be able to attract NK cells from surrounding tissues or peripheral blood. We developed a novel live mouse imaging system-based NK-cell migration test, and demonstrated for the first time that human Ad.DC induced directional migration of human NK cells across subcutaneous tissues, indicating that Ad.DC-NK cell contact and interaction could occur in vivo. We examined the mechanism of Ad.DC-induced migration of NK cells in vitro and in vivo. Ad.DC produced multiple chemokines previously reported to recruit NK cells, including immunoregulatory CXCL10/IP-10 and proinflammatory CXCL8/IL-8. In vitro chemotaxis experiments utilizing neutralizing antibodies and recombinant human chemokines showed that CXCL10/IP-10 and CXCL8/IL-8 were critical for Ad.DC-mediated recruitment of CD56 hi CD16 - and CD56 lo CD16 + NK cells, respectively. The importance of CXCL8/IL-8 was further demonstrated in vivo. Pretreatment of mice with the neutralizing anti-CXCL8/IL-8 antibody led to significant inhibition of Ad.DC-induced migration of NK cells in vivo. These data show that Ad.DC can recruit spatially distant NK cells toward a vaccine site via specific chemokines. Therefore, an Ad.DC vaccine can likely induce interaction with endogenous NK cells via transmembrane mediators, and consequently mediate Th1 polarization and amplification of immune functions in vivo.

Molecular mimicry of MAGE-A6 andMycoplasma penetransHF-2 epitopes in the induction of antitumor CD8+T-cell responses

“…Type-1 polarizing mature dendritic cells (mDC), which we have previously shown to be potent mediators of both adaptive and innate Type-1 immunities, [42][43][44] could be a potent immunization platform for enhancing cross-reactive immunity and treating patients harboring MAGE-A6 C malignancies. Given the link between clinical Mycoplasma infections and pulmonary disease, 34 and taken together with circumstantial reports of spontaneous cancer regression in patients (particularly of hematologic malignancies) recovering from pneumonia, 45,46 it is tempting to consider the possible involvement of exploiting cross-reactive immunity in these complex biological processes.…”

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

“…Reciprocally, DC, when stimulated by pathogens or TLR ligands, constitutes a key source of cytokines (such as IL-12, IL-18, IL-15) known to regulate NK-cell proliferation, cytotoxicity, and cytokine production [31,33]. DC produces also a number of biologically significant chemokines such as CXCL8/IL-8, CXCL9, CXCL10, and CXCL11 capable of stimulating NK-cell migrations [34,35]. Efficient recruitment of NK cells to peripheral organs or inflamed LNs via direct or indirect interaction with DC is therefore essential in NK-cell-mediated immune surveillance.…”

IFNα signaling through PKC-θ is essential for antitumor NK cell function

“…48 CXCL10 is a chemokine involved in NK cell recruitment to inflamed tissues and sites of tumor development. [49][50][51] In fact, it has recently been demonstrated that the efficacy of adenovirusengineered dendritic cells as a cancer vaccine correlates with their ability to secrete CXCL10 and CXCL8 and to efficiently recruit antitumor NK cells. 51 CXCL10 secretion has been, so far, primarily attributed to DCs and monocytes/macrophages.…”

“…[49][50][51] In fact, it has recently been demonstrated that the efficacy of adenovirusengineered dendritic cells as a cancer vaccine correlates with their ability to secrete CXCL10 and CXCL8 and to efficiently recruit antitumor NK cells. 51 CXCL10 secretion has been, so far, primarily attributed to DCs and monocytes/macrophages. 50,51 Our data indicate that NK cells also secrete CXCL10 upon IFNa treatment, albeit at a lower concentrations than DCs and macrophages.…”

“…51 CXCL10 secretion has been, so far, primarily attributed to DCs and monocytes/macrophages. 50,51 Our data indicate that NK cells also secrete CXCL10 upon IFNa treatment, albeit at a lower concentrations than DCs and macrophages. Furthermore, in a recent transcriptomic analysis we found that NK cell activation by target cells in the presence of whole peripheral blood mononuclear cells (PBMCs) induces the expression of CXCL10, as well as its receptor CXCR3, suggesting the presence of an autocrine migration loop occurring during NK cell activation.…”