to interferon-γ. When they introduced specific APLNR mutations found in some patient tumors into a melanoma cell line, T cells were less effective at targeting the tumor cells. The same was true when they inactivated APLNR in melanoma tumors in mice. When Restifo and his team sequenced tumors from patients whose melanomas were resistant to immunotherapies, they found 7 different mutations in the APLNR gene. “The methods used in this study are outstanding—a real molecular tour de force,” said Jeffrey Weber, MD, PhD, who was not involved with the research and is the deputy director of NYU Langone’s Perlmutter Cancer Center. “The findings reinforce the idea that interferon-γ pathway signaling and the JAK-STAT pathway are critically needed for adequate recognition of tumor cells by effector T cells, and suggest that when those elements are lacking in tumors that they somehow need to be replaced [to restore immune surveillance].” Restifo suspects that the other tumor cell mutations found in the CRISPR screen may require a different approach to restore tumor vulnerability. “There is unlikely to be a single fix,” Restifo said. “To make immunotherapy effective for more patients, we may need to develop a new category of drugs that circumvent these escape mechanisms.”

中文翻译：

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共和党人将拥有 ACA 和医疗改革的一切

干扰素-γ。当他们将在某些患者肿瘤中发现的特定 APLNR 突变引入黑色素瘤细胞系时，T 细胞在靶向肿瘤细胞方面的效果较差。当他们在小鼠黑色素瘤肿瘤中灭活 APLNR 时也是如此。当 Restifo 和他的团队对黑色素瘤对免疫疗法有抵抗力的患者的肿瘤进行测序时，他们在 APLNR 基因中发现了 7 个不同的突变。“这项研究中使用的方法非常出色——真正的分子杰作，”杰弗里·韦伯 (Jeffrey Weber) 医学博士说，他没有参与这项研究，并且是纽约大学朗格尼珀尔马特癌症中心的副主任。“这些发现强化了这样一种观点，即干扰素-γ 通路信号和 JAK-STAT 通路是效应 T 细胞充分识别肿瘤细胞所必需的，并建议当肿瘤中缺乏这些元素时，它们需要以某种方式被替换[以恢复免疫监视]。” Restifo 怀疑在 CRISPR 筛选中发现的其他肿瘤细胞突变可能需要不同的方法来恢复肿瘤易损性。“不太可能有一个单一的解决方案，” Restifo 说。“为了使免疫疗法对更多患者有效，我们可能需要开发一种新型药物来规避这些逃逸机制。”