IFN-γ 信号使黑色素瘤细胞对 BH3 模拟物敏感。
IFN-γ Signaling Sensitizes Melanoma Cells to BH3 Mimetics.
机构信息
Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia; Department of Medical Oncology, Mater Hospital, Sydney, Australia.
出版信息
J Invest Dermatol. 2023 Jul;143(7):1246-1256.e8. doi: 10.1016/j.jid.2023.01.017. Epub 2023 Feb 1.
Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor-based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and interactions of apoptotic regulators MCL-1, NOXA, and BAK. The addition of pro-apoptotic BH3 mimetic drugs sensitized PD1 PROG melanoma cells to apoptosis in response to IFN-γ or autologous immune cell activation. These findings provide translatable strategies for combination therapies in melanoma.
免疫疗法针对 PD-1 和/或 CTLA4 可使一部分黑色素瘤患者获得持久的反应。然而，许多患者对这些免疫检查点抑制剂没有反应，多达 60%的应答患者会产生治疗抵抗。我们描述了一种由免疫细胞活性驱动的黑色素瘤的脆弱性，为提供额外的治疗选择提供了途径。本研究评估了源自黑色素瘤转移的短期黑色素瘤细胞系（称为 PD1 PROG 细胞），这些细胞在基于 PD-1 抑制剂的治疗中进展。我们表明，细胞因子 IFN-γ 通过促进凋亡调节剂 MCL-1、NOXA 和 BAK 的积累和相互作用的改变，使黑色素瘤细胞对凋亡敏感。添加促凋亡 BH3 模拟药物可使 PD1 PROG 黑色素瘤细胞对 IFN-γ 或自体免疫细胞激活的凋亡敏感。这些发现为黑色素瘤的联合治疗提供了可转化的策略。
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