Immunotherapy Resistance by Inflammation-Induced Dedifferentiation.
Immunotherapy Resistance by Inflammation-Induced Dedifferentiation.
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DOI：
10.1158/2159-8290.cd-17-1178
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发表时间：
2018-08
期刊：
影响因子：
28.2
通讯作者：
Ribas A
中科院分区：
文献类型：
--
作者：
Mehta A;Kim YJ;Robert L;Tsoi J;Comin-Anduix B;Berent-Maoz B;Cochran AJ;Economou JS;Tumeh PC;Puig-Saus C;Ribas A
在过去的十年中，出现了一种有希望的转移性黑色素瘤靶向和免疫治疗方法。有了这些疗法，我们现在面临着肿瘤获得性耐药的新机制。我们在这里报告一个病人的转移性黑色素瘤进行去分化作为一种耐药机制过继性T细胞转移疗法（ACT）的MART-1抗原，这种现象只在小鼠研究中观察到的日期。在肿瘤消退的初始阶段后，患者出现复发，肿瘤缺乏黑素细胞抗原（MART-1，gp 100）并表达炎症诱导的神经嵴标志物（NGFR）。我们使用人黑色素瘤细胞系证明，这种耐药表型可以通过用表达MART-1 T细胞受体的T细胞或TNFα处理在体外诱导，并且该表型随着炎症刺激的消退而可逆。这支持了对癌症免疫疗法的获得性抗性可以由炎症诱导的癌症去分化介导的假设。
A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T cell transfer therapy (ACT) to the MART-1 antigen, a phenomenon that had only been observed in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART-1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART-1 T-cell receptor expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.