Allogeneic NK cells induce the in vitro activation of monocyte-derived and conventional type-2 dendritic cells and trigger an inflammatory response under cancer-associated conditions.

IF 3.4 3区 医学 Q3 IMMUNOLOGY
E C Toffoli, A A van Vliet, C Forbes, A J Arns, H W M Verheul, J Tuynman, H J van der Vliet, J Spanholtz, T D de Gruijl
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Abstract

Natural killer (NK) cells are innate lymphocytes capable to recognize and kill virus-infected and cancer cells. In the past years, the use of allogeneic NK cells as anti-cancer therapy gained interest due to their ability to induce graft-versus-cancer responses without causing graft-versus-host disease and multiple protocols have been developed to produce high numbers of activated NK cells. While the ability of these cells to mediate tumor kill has been extensively studied, less is known about their capacity to influence the activity of other immune cells that may contribute to a concerted anti-tumor response in the tumor microenvironment (TME). In this study, we analyzed how an allogeneic off-the-shelf cord blood stem cell-derived NK-cell product influenced the activation of dendritic cells (DC). Crosstalk between NK cells and healthy donor monocyte-derived DC (MoDC) resulted in the release of IFNγ and TNF, MoDC activation, and the release of the T-cell-recruiting chemokines CXCL9 and CXCL10. Moreover, in the presence of prostaglandin-E2, NK cell/MoDC crosstalk antagonized the detrimental effect of IL-10 on MoDC maturation leading to higher expression of multiple (co-)stimulatory markers. The NK cells also induced activation of conventional DC2 (cDC2) and CD8+ T cells, and the release of TNF, GM-CSF, and CXCL9/10 in peripheral blood mononuclear cells of patients with metastatic colorectal cancer. The activated phenotype of MoDC/cDC2 and the increased release of pro-inflammatory cytokines and T-cell-recruiting chemokines resulting from NK cell/DC crosstalk should contribute to a more inflamed TME and may thus enhance the efficacy of T-cell-based therapies.

异体 NK 细胞可诱导单核细胞衍生细胞和传统 2 型树突状细胞的体外活化,并在癌症相关条件下引发炎症反应。
自然杀伤(NK)细胞是一种先天性淋巴细胞,能够识别并杀死受病毒感染的细胞和癌细胞。在过去几年中,由于异体 NK 细胞能够诱导移植物抗癌反应而不会引起移植物抗宿主病,因此将其用作抗癌疗法受到了人们的关注。虽然对这些细胞介导肿瘤杀伤的能力进行了广泛研究,但对它们影响其他免疫细胞活性的能力却知之甚少,而这些免疫细胞可能有助于肿瘤微环境中的协同抗肿瘤反应。在这项研究中,我们分析了异体现成脐带血干细胞衍生的NK细胞产品如何影响树突状细胞(DC)的活化。NK细胞与健康供体单核细胞衍生的DC(MoDC)之间的相互作用导致了IFNγ和TNF的释放、MoDC的活化以及T细胞募集趋化因子CXCL9和CXCL10的释放。此外,在前列腺素-E2存在的情况下,NK细胞/MoDC串联拮抗了IL-10对MoDC成熟的不利影响,导致多种(共)刺激标志物的更高表达。NK 细胞还诱导了传统 DC2(cDC2)和 CD8+ T 细胞的活化,以及转移性结直肠癌患者外周血单核细胞中 TNF、GM-CSF 和 CXCL9/10 的释放。MoDC/cDC2的活化表型以及NK细胞/DC串扰导致的促炎细胞因子和T细胞募集趋化因子的释放增加,应有助于使TME更加炎症,从而提高基于T细胞疗法的疗效。
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来源期刊
CiteScore
8.40
自引率
2.20%
发文量
101
审稿时长
3-8 weeks
期刊介绍: Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice. The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.
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