SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint
SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint
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DOI：
10.7554/elife.52539
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发表时间：
2020-03-03
期刊：
影响因子：
7.7
通讯作者：
Lotem, Michal
中科院分区：
文献类型：
--
作者：
Hajaj, Emma;Eisenberg, Galit;Lotem, Michal
SLAMF 6是Ig超家族的同型受体，其在免疫调节中的确切作用仍然难以捉摸。其在静息和活化T细胞上的组成性表达使其不能成为真正的耗竭标志物。通过使Pmel-1小鼠与SLAMF 6-/-小鼠交配，我们产生了缺乏SLAMF 6并表达gp 100黑色素瘤抗原的转基因TCR的T细胞的供体。活化的Pmel-1xSLAMF 6-/-CD 8 + T细胞显示出改善的多功能性和强的肿瘤细胞溶解。T-bet是Pmel-1 x SLAMF 6-/-细胞中的主导转录因子，并且在激活后，它们获得效应记忆表型。将Pmel-1 x SLAMF 6-/- T细胞过继转移至荷黑色素瘤小鼠导致持久的肿瘤消退，而Pmel-1 T细胞则获得了暂时的反应。LAG-3表达在SLAMF 6-/-细胞中升高，并且向过继转移方案中添加LAG-3阻断抗体改善了SLAMF 6-/- T细胞并甚至进一步加速了抗肿瘤应答。这项研究的结果支持了SLAMF 6是一种抑制性免疫受体的观点，它的缺失使强大的CD 8 + T细胞能够根除肿瘤。
SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 -/- mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100melanoma antigen. Activated Pmel-1xSLAMF6 -/- CD8+ T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1 x SLAMF6 -/- cells, and upon activation, they acquired an effector-memory phenotype. Adoptive transfer of Pmel-1 x SLAMF6 -/- T cells to melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. LAG-3 expression was elevated in the SLAMF6 -/- cells, and the addition of the LAG-3-blocking antibody to the adoptive transfer protocol improved the SLAMF6 -/- T cells and expedited the antitumor response even further. The results from this study support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8+ T cells to eradicate tumors.