Department of Pathology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
Departments of Immunology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
Commun Biol. 2023 Aug 4;6(1):815. doi: 10.1038/s42003-023-05169-3.
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 CD8T and CD4T 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.
三阴性乳腺癌（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。在这里，我们表明，携带表面 PD-L1、PD-1、Fas、FasL、TRAIL、CTLA-4 和 TGF-β1 的肿瘤细胞衍生的外泌体（TEX）诱导 CD8T 和 CD4T 细胞凋亡，但不影响 B 和 NK 细胞。阻断 TEX 诱导的受体/配体信号的抑制剂以及用蛋白酶 K 或热预处理 TEX 均不能防止 T 细胞凋亡。细胞松弛素 D、Dynosore 或 Pit Stop 2 部分抑制 TEX 的摄取，但不能防止 T 细胞凋亡。TEX 进入 T 细胞诱导线粒体中的细胞色素 C 和 Smac 释放，并在细胞质中切割 caspase-3 和 PARP。凋亡的 T 细胞中存活蛋白的表达减少。无论是否存在外部死亡受体信号，TEX 进入 T 细胞都会引发线粒体应激，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 TEX 的丰度对过继转移的 T 细胞构成威胁，限制了它们的治疗潜力。
