Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Cancer Discov. 2018 Aug;8(8):935-943. doi: 10.1158/2159-8290.CD-17-1178. Epub 2018 Jun 13.
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 MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced by treatment with MART1 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. We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. .
在过去的十年中，针对转移性黑色素瘤的靶向治疗和免疫疗法已经有了很大的进展。随着这些疗法的出现，我们现在面临着肿瘤获得性耐药的新机制。我们在此报告了一位转移性黑色素瘤患者，其肿瘤发生去分化，成为对 MART1 抗原的过继性 T 细胞转移治疗（ACT）的耐药机制，这一现象迄今为止仅在小鼠研究中观察到。在最初的肿瘤消退期后，该患者复发，肿瘤缺乏黑色素细胞抗原（MART1、gp100），并表达炎症诱导的神经嵴标记物（NGFR）。我们利用人黑色素瘤细胞系证明，这种耐药表型可通过表达 MART1 T 细胞受体的 T 细胞或 TNFα 诱导，并且在炎症刺激物撤回后可逆转表型。这支持了这样一种假说，即癌症免疫疗法的获得性耐药可以通过炎症诱导的癌症去分化来介导。我们报告了一位转移性黑色素瘤患者，其肿瘤发生炎症诱导的去分化，成为对 MART1 抗原的 ACT 的耐药机制。我们的结果表明，未来的黑色素瘤 ACT 方案可能受益于同时针对多个肿瘤抗原，调节炎症反应，以及抑制炎症诱导的去分化信号。
