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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
ShinLa Shu, Junko Matsuzaki, Muzamil Y. Want, Alexis Conway, Shawna Benjamin-Davalos, Cheryl L. Allen, Marina Koroleva, Sebastiano Battaglia, Adekunle Odunsi, Hans Minderman, Marc S. Ernstoff

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:

黑色素瘤来源的外来体对NY-ESO-1抗原特异性人类CD8 + T细胞的免疫抑制作用取决于IL-10,并且不依赖于黑色素瘤细胞系中的BRAFV600E突变。

已知包括人类黑素瘤来源的外来体(HMEX)在内的外来体会抑制免疫效应细胞的功能,对于HMEX,这种效应与免疫检查点配体PD-L1的表面存在有关。这项研究调查了黑色素瘤细胞的BRAF突变状态与抗原特异性人T细胞对分泌型HMEX外泌体的抑制之间的关系。从两个黑色素瘤细胞系2183-Her4和888-mel中分离出外泌体,它们是野生型的BRAF WT和BRAF V600E, 分别。使用改良的尺寸排阻色谱法(SEC)分离HMEX,结果表明与超速离心分离相比,该混合物可减少非外泌体相关细胞因子的共分离。在体外测试了外泌体对受NY-ESO-1抗原攻击的患者来源的NY-ESO-1特异性CD8 + T细胞的免疫抑制作用。来自两种细胞系的HMEX都可同等地抑制抗原特异性T细胞的免疫反应,这可通过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已被证明是维持BRAF V600E突变细胞中增强的肿瘤发生的关键途径。黑色素瘤细胞。因此,我们证明了HMEX抑制了抗原特异性T细胞反应,而与亲本细胞的BRAF突变状态无关。另外,PD-L1和IL-10有助于HMEX介导的抗原特异性人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细胞的功效的疗法时,应考虑外泌体的抑制能力。

更新日期:2020-08-17
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