Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming
Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming
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受辐射的肿瘤细胞衍生的微粒通过细胞杀伤和免疫重编程介导肿瘤根除
DOI：
10.1126/sciadv.aay9789
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发表时间：
2020-03-01
期刊：
影响因子：
13.6
通讯作者：
Yang, Kunyu
中科院分区：
文献类型：
--
作者：
Wan, Chao;Sun, Yajie;Yang, Kunyu
放射疗法（RT）是常规用于癌症治疗，但其临床适应症的扩展仍然具有挑战性。辐射诱导的旁观者效应（里贝）的机制尚未被理解，也没有在治疗上加以利用。我们认为，里贝主要是介导的辐射肿瘤细胞释放微粒（RT-MP），诱导广泛的抗肿瘤作用，并导致免疫原性死亡，主要是通过铁凋亡。使用小鼠恶性胸腔积液（MPE）模型，我们证明了RT-MP极化微环境M2肿瘤相关巨噬细胞（M2-TAMs）M1-TAMs和调制TAMs和肿瘤细胞之间的抗肿瘤相互作用。RT-MP内化后，TAM显示程序性细胞死亡配体1（PD-L1）表达增加，增强了后续联合抗PD-1治疗，对MPE和顺铂耐药MPE小鼠模型产生消融作用。诱导免疫记忆效应。
Radiotherapy (RT) is routinely used in cancer treatment, but expansion of its clinical indications remains challenging. The mechanism underlying the radiation-induced bystander effect (RIBE) is not understood and not therapeutically exploited. We suggest that the RIBE is predominantly mediated by irradiated tumor cell-released microparticles (RT-MPs), which induce broad antitumor effects and cause immunogenic death mainly through ferroptosis. Using a mouse model of malignant pleural effusion (MPE), we demonstrated that RT-MPs polarized microenvironmental M2 tumor-associated macrophages (M2-TAMs) to M1-TAMs and modulated antitumor interactions between TAMs and tumor cells. Following internalization of RT-MPs, TAMs displayed increased programmed cell death ligand 1 (PD-L1) expression, enhancing follow-up combined anti-PD-1 therapy that confers an ablative effect against MPE and cisplatin-resistant MPE mouse models. Immunological memory effects were induced.