PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of immune inhibitory-related molecules
PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of immune inhibitory-related molecules
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PAX5单倍体不足通过免疫抑制相关分子的高表达诱导CD8 T细胞功能障碍或耗竭
DOI：
10.1016/j.ctarc.2021.100437
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发表时间：
2021
影响因子：
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通讯作者：
周建峰
中科院分区：
文献类型：
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作者：
梁密;龚端豪;王磊;梁雪;孟姣;黄伟;周建峰
目的：PAX 5单倍缺陷促进肿瘤发生与免疫逃逸有关。但PAX 5突变诱导肿瘤免疫逃逸的机制尚未阐明。我们的目的是研究PAX 5单倍不足如何影响肿瘤微环境中的效应CD 8 + T细胞。方法：我们利用CIBERSORT算法，根据PAX 5突变的儿童B-急性淋巴细胞白血病（B-ALL）的基因表达谱（GEPs），估计了22种免疫细胞类型的比例和免疫毒性相关分子的表达。我们构建了PAX 5单倍缺失的A20细胞系，建立了A20移植瘤模型，并评价了PAX 5单倍缺失对肿瘤微环境（TME）中免疫相关分子的影响。结果：结果表明，PAX 5突变的B-ALL患儿骨髓中T细胞百分率与无PAX 5突变的B-ALL患儿骨髓中T细胞百分率除滤泡辅助性T细胞（Tfh）外，无统计学差异。但在PAX 5基因突变的儿童B- ALL患者骨髓中发现了多种上调的免疫毒性相关分子。通过不同的方法，我们发现PAX 5单倍缺失克隆TME中的几种CD 8 + T细胞免疫相关分子如TIM 3、NR 4A 1和BATF与PAX 5野生型对照相比显著增加。PAX 5单倍缺失肿瘤TME中CD 8 + T细胞的IFN-γ水平较PAX 5野生型对照组显著降低。结论：我们的研究表明PAX 5单倍不足通过TIM 3、NR 4A 1和BATF在TME的CD 8 + T细胞中的高表达诱导CD 8 + T细胞功能障碍或衰竭。
Purpose: PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape. But the mechanisms of .PAX5 mutations inducing tumor immune escape have not been clarified. Our aim was to study how PAX5 .haploinsufficiency influences effector CD8 + T cells in tumor microenvironment. .Methods: We estimated the proportions of 22 immune cell types and the expressions of immune inhibitory-related .molecules based on gene expression profiles (GEPs) from children’s B- acute lymphoblastic leukemia(B-ALL) with .PAX5 mutations by CIBERSORT, an established algorithm. We constructed the PAX5 haplodeletion A20 cell lines, .built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on immune inhibitory-related .molecules in the tumor microenvironment (TME). .Results: Our results indicated the percentages of T cells in bone marrow of children’s B-ALL with PAX5 mutations .were not statistically different from that in bone marrow of B-ALL without PAX5 mutations, except for T .follicular helper (Tfh) cells. But a variety of up-regulated immune inhibitory-related molecules in bone marrow .of children’s B- ALL with PAX5 mutations were identified. By different approaches, we found that several immune inhibitory-related molecules of CD8+ T cells in TME of PAX5 haplodeletion clones such as TIM3, NR4A1 .and BATF, were increased significantly compared with that of PAX5 wild type control. The IFN-ɤ of CD8+ T cells .in TME of PAX5 haplodeletion tumors was decreased significantly compared with that of PAX5 wild type control. .Conclusion: Our study showed that PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by .high expression of TIM3, NR4A1 and BATF in the CD8+ T cells of TME.