Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion
Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion
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DOI：
10.15252/embj.201490786
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发表时间：
2015-08-04
期刊：
影响因子：
11.4
通讯作者：
Verdeil, Gregory
中科院分区：
文献类型：
--
作者：
Giordano, Marilyn;Henin, Coralie;Verdeil, Gregory
T细胞浸润性肿瘤表达慢性病毒刺激的T细胞的典型表面分子，通常称为“耗尽”T细胞。我们比较了浸润原位黑色素瘤的“耗尽”CD 8 T细胞与幼稚和急性刺激的CD 8 T细胞的转录组。尽管肿瘤和病毒诱导的耗尽的CD 8 T细胞的转录特征之间有很强的相似性，但出现了显著的差异。在转录调节因子中，Nr 4a 2和Maf在肿瘤耗竭的T细胞中高度过表达，并且在来自人黑素瘤转移的CD 8 T细胞中显著上调。转导小鼠肿瘤特异性CD 8 T细胞表达Maf部分再现了与肿瘤诱导的耗竭相关的转录程序。在过继转移后，转导的细胞表现出正常的稳态，但未能在荷瘤宿主中积累，并产生有缺陷的抗肿瘤效应子应答。我们进一步鉴定了TGF β和IL-6作为CD 8 T细胞中Maf表达的主要诱导物，并表明Maf缺失的肿瘤特异性CD 8 T细胞在体内抑制肿瘤生长的效力要强得多。因此，黑色素瘤微环境有助于CD 8 T细胞分化程序的偏斜，部分是通过TGF β/IL-6介导的Maf诱导。
T cells infiltrating neoplasms express surface molecules typical of chronically virus-stimulated T cells, often termed "exhausted" T cells. We compared the transcriptome of "exhausted" CD8 T cells infiltrating autochthonous melanomas to those of naive and acutely stimulated CD8 T cells. Despite strong similarities between transcriptional signatures of tumor-and virus-induced exhausted CD8 T cells, notable differences appeared. Among transcriptional regulators, Nr4a2 and Maf were highly overexpressed in tumor-exhausted T cells and significantly upregulated in CD8 T cells from human melanoma metastases. Transduction of murine tumor-specific CD8 T cells to express Maf partially reproduced the transcriptional program associated with tumor-induced exhaustion. Upon adoptive transfer, the transduced cells showed normal homeostasis but failed to accumulate in tumor-bearing hosts and developed defective antitumor effector responses. We further identified TGF beta and IL-6 as main inducers of Maf expression in CD8 T cells and showed that Maf-deleted tumor-specific CD8 T cells were much more potent to restrain tumor growth in vivo. Therefore, the melanoma microenvironment contributes to skewing of CD8 T cell differentiation programs, in part by TGF beta/IL-6-mediated induction of Maf.