Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells.
Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells.
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DOI：
10.1038/s42003-023-05169-3
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发表时间：
2023-08-04
影响因子：
5.9
通讯作者：
Whiteside, Theresa L. L.
中科院分区：
文献类型：
--
作者：
Mondal, Sujan Kumar;Haas, Derick;Han, Jie;Whiteside, Theresa L. L.
TNBC患者血浆中的小细胞外囊泡（sEV）促进T细胞功能障碍和肿瘤进展。我们发现肿瘤细胞来源的外泌体（TEX）携带表面PDL-1、PD-1、Fas、FasL、TRAIL、CTLA-4和TGF-β1诱导CD 8 +T和CD 4 +T细胞凋亡，但不影响B和NK细胞。阻断TEX诱导的受体/配体信号的抑制剂和用蛋白酶K或热进行TEX预处理不能防止T细胞凋亡。细胞松弛素D、Dynosore或Pit Stop 2部分抑制TEX摄取，但不阻止T细胞凋亡。TEX进入T细胞诱导细胞色素C和Smac从线粒体释放以及细胞质中的半胱天冬酶-3和PARP裂解。在经历凋亡的T细胞中，存活蛋白的表达减少。不依赖于外部死亡受体信号传导，TEX进入T细胞诱导线粒体应激，引发无情的内在凋亡，这是导致荷瘤宿主中活化T细胞死亡的原因。癌症血浆中大量的TEX代表了过继转移T细胞的危险，限制了它们的治疗潜力。由受体T细胞摄取的来自三阴性乳腺癌细胞的肿瘤细胞来源的外泌体诱导内在细胞凋亡，导致细胞死亡，这对过继性癌症免疫治疗有影响。
Small extracellular vesicles (sEV) in TNBC patients’ plasma promote T cell dysfunction and tumor progression. Here we show that tumor cell-derived exosomes (TEX) carrying surface PDL-1, PD-1, Fas, FasL, TRAIL, CTLA-4 and TGF-β1 induce apoptosis of CD8+T and CD4+T cells but spare B and NK cells. Inhibitors blocking TEX-induce receptor/ligand signals and TEX pretreatments with proteinase K or heat fail to prevent T cell apoptosis. Cytochalasin D, Dynosore or Pit Stop 2, partly inhibit TEX uptake but do not prevent T cell apoptosis. TEX entry into T cells induces cytochrome C and Smac release from mitochondria and caspase-3 and PARP cleavage in the cytosol. Expression of survival proteins is reduced in T cells undergoing apoptosis. Independently of external death receptor signaling, TEX entry into T cells induces mitochondrial stress, initiating relentless intrinsic apoptosis, which is responsible for death of activated T cells in the tumor-bearing hosts. The abundance of TEX in cancer plasma represents a danger for adoptively transferred T cells, limiting their therapeutic potential. Tumor cell-derived exosomes from triple negative breast cancer cells that are taken up by recipient T cells induce intrinsic apoptosis, leading to cell death, with implications for adoptive cancer immunotherapy.
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影响因子：
7.4
作者：
Marleau AM;Chen CS;Joyce JA;Tullis RH
通讯作者：
Tullis RH
影响因子：
3.4
作者：
Dominkus, Pia Puzar;Stenovec, Matjaz;Lenassi, Metka
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作者：
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通讯作者：
Whiteside, Theresa L.
DOI：
10.1073/pnas.0804543106
发表时间：
2009-03-10
影响因子：
11.1
作者：
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通讯作者：
Rak, Janusz
影响因子：
8.4
作者：
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通讯作者：
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