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An Immunosuppressive Effect of Melanoma-derived Exosomes on NY-ESO-1 Antigen-specific Human CD8+ T Cells is Dependent on IL-10 and Independent of BRAFV600E Mutation in Melanoma Cell Lines.
Immunological Investigations ( IF 2.9 ) Pub Date : 2020-08-17 , DOI: 10.1080/08820139.2020.1803353
ShinLa Shu 1 , Junko Matsuzaki 2 , Muzamil Y Want 2 , Alexis Conway 3 , Shawna Benjamin-Davalos 1 , Cheryl L Allen 1 , Marina Koroleva 1 , Sebastiano Battaglia 2 , Adekunle Odunsi 2 , Hans Minderman 3 , Marc S Ernstoff 1
Affiliation  

ABSTRACT

Exosomes, including human melanoma-derived exosomes (HMEX), are known to suppress the function of immune effector cells, which for HMEX has been associated with the surface presence of the immune checkpoint ligand PD-L1. This study investigated the relationship between the BRAF mutational status of melanoma cells and the inhibition of secreted HMEX exosomes on antigen-specific human T cells. Exosomes were isolated from two melanoma cell lines, 2183-Her4 and 888-mel, which are genetically wild-type BRAFWT and BRAFV600E, respectively. HMEX were isolated using a modified, size-exclusion chromatography (SEC) method shown to reduce co-isolation of non-exosome-associated cytokines compared to ultracentrifugation isolation. The immunoinhibitory effect of the exosomes was tested in vitro on patient-derived NY-ESO-1-specific CD8+ T cells challenged with NY-ESO-1 antigen. HMEX from both cell lines inhibited the immune response of antigen-specific T cells comparably, as evidenced by the reduction of IFN-γ and TNF-α in NY-ESO-1 tetramer-positive cells. This inhibition could be partially reversed by the presence of anti-PD-L1 and anti-IL-10 antibodies. IL-10 has been demonstrated to be a critical pathway for sustaining enhanced tumorigenesis in BRAFV600E mutant cells compared to BRAFWT melanoma cells. Thus, we demonstrate that HMEX inhibit antigen-specific T cell responses independent of the BRAF mutational status of the parent cells. In addition, PD-L1 and IL-10 contribute to the HMEX-mediated immunosuppression of antigen-specific human T cells. The inhibitory capacity of exosomes should be taken into consideration when developing therapies that are reliant upon the potency of customized, antigen-specific effector T cells.



中文翻译:

黑色素瘤衍生的外泌体对 NY-ESO-1 抗原特异性人 CD8+ T 细胞的免疫抑制作用依赖于 IL-10,不依赖于黑色素瘤细胞系中的 BRAFV600E 突变。

摘要

已知外泌体,包括人类黑色素瘤衍生的外泌体 (HMEX) 会抑制免疫效应细胞的功能,对于 HMEX,这与免疫检查点配体 PD-L1 的表面存在有关。本研究调查了黑色素瘤细胞的 BRAF 突变状态与分泌的 HMEX 外泌体对抗原特异性人类 T 细胞的抑制之间的关系。从两种黑色素瘤细胞系 2183-Her4 和 888-mel 中分离出外泌体,它们是基因野生型 BRAF WT和 BRAF V600E, 分别。HMEX 使用改进的尺寸排阻色谱 (SEC) 方法进行分离,与超速离心分离相比,该方法显示可减少非外泌体相关细胞因子的共分离。外泌体的免疫抑制作用在体外对用 NY-ESO-1 抗原攻击的患者衍生的 NY-ESO-1 特异性 CD8 + T 细胞进行了测试。来自两种细胞系的 HMEX 可相当地抑制抗原特异性 T 细胞的免疫反应,这可以通过 NY-ESO-1 四聚体阳性细胞中 IFN-γ 和 TNF-α 的减少来证明。抗 PD-L1 和抗 IL-10 抗体的存在可以部分逆转这种抑制作用。与 BRAF WT相比, IL-10 已被证明是在 BRAF V600E突变细胞中维持增强的肿瘤发生的关键途径黑色素瘤细胞。因此,我们证明 HMEX 抑制抗原特异性 T 细胞反应,而与亲本细胞的 BRAF 突变状态无关。此外,PD-L1 和 IL-10 有助于 HMEX 介导的抗原特异性人类 T 细胞的免疫抑制。在开发依赖于定制的抗原特异性效应 T 细胞效力的疗法时,应考虑外泌体的抑制能力。

更新日期:2020-10-12
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