肿瘤细胞治疗研究
英文原题：CD98hc promotes drug resistance in extranodal natural killer/T cell lymphoma through tumor cell-derived small extracellular vesicles.
这些数据表明，在ENKTL治疗中靶向CD98hc可能有助于克服耐药性。
结外自然杀伤/T细胞淋巴瘤（ENKTL）在放化疗后复发率高。耐药可由小细胞外囊泡（sEVs）的货物介导。在此，我们发现肿瘤细胞和血清sEVs中跨膜糖蛋白CD98hc的高丰度与ENKTL进展和耐药相关。机制上，PEG化天冬酰胺酶（PEG-asp）治疗——一种针对ENKTL的常用疗法——促进转录因子ATF4转位至细胞核，在核内ATF4被USP1稳定，随后增加CD98hc表达。肿瘤细胞来源sEVs中递送的CD98hc在培养的人NK淋巴瘤细胞系、动物模型以及难治/复发ENKTL患者样本中增加了肿瘤细胞增殖和耐药。此外，同时抑制USP1和EV分泌协同增强了PEG-asp的细胞毒性。这些数据表明，在ENKTL治疗中靶向CD98hc可能有助于克服耐药。
Extranodal natural killer/T cell lymphoma (ENKTL) shows a high rate of recurrence after chemoradiotherapy. Drug resistance can be mediated by the cargo of small extracellular vesicles (sEVs). Here, we show that high abundance of the transmembrane glycoprotein CD98hc in tumor cells and serum sEVs was associated with ENKTL progression and drug resistance. Mechanistically, PEGylated-asparaginase (PEG-asp) treatment, a common therapy against ENKTL, promoted the translocation of the transcription factor ATF4 to the nucleus, where it was stabilized by USP1 and subsequently increased CD98hc expression. CD98hc delivered in tumor cell-derived sEVs increased tumor cell proliferation and drug resistance in a cultured human NK lymphoma cell line, animal models, and samples from patients with refractory/relapse ENKTL. Moreover, inhibiting both USP1 and EV secretion synergistically enhanced the cytotoxicity of PEG-asp. These data suggest that targeting CD98hc in the treatment of ENKTL may be beneficial in overcoming drug resistance.
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