Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland; Agora Translational Cancer Research Center, 1005 Lausanne, Switzerland.
Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), 1015 Lausanne, Switzerland.
Cell Stem Cell. 2023 Jun 1;30(6):818-831.e6. doi: 10.1016/j.stem.2023.05.007.
Despite the remarkable success of immune checkpoint blockade (ICB) therapy, most cancer patients still do not respond. We now find that immunotherapy can induce stem-like properties in tumors. Using mouse models of breast cancer, we observe that cancer stem cells (CSCs) show not only enhanced resistance to T cell cytotoxicity, but that interferon gamma (IFNγ) produced by activated T cells directly converts non-CSCs to CSCs. IFNγ enhances several CSC phenotypes, such as resistance to chemo- and radiotherapy and metastasis formation. We identified the branched-chain amino acid aminotransaminase 1 (BCAT1) as a downstream mediator of IFNγ-induced CSC plasticity. Targeting BCAT1 in vivo improved cancer vaccination and ICB therapy by preventing IFNγ-induced metastasis formation. Breast cancer patients treated with ICB exhibited a similar increase in CSC markers expression indicating comparable responses to immune activation in humans. Collectively, we discover an unexpected, pro-tumoral role for IFNγ that may contribute to cancer immunotherapy failure.
尽管免疫检查点阻断 (ICB) 疗法取得了显著成功，但大多数癌症患者仍未响应。我们现在发现免疫疗法可以在肿瘤中诱导出类似干细胞的特性。使用乳腺癌的小鼠模型，我们观察到癌症干细胞 (CSC) 不仅表现出对 T 细胞细胞毒性的增强抗性，而且激活的 T 细胞产生的干扰素 γ (IFNγ) 可直接将非 CSC 转化为 CSC。IFNγ 增强了几种 CSC 表型，如对化疗和放疗的抗性以及转移形成。我们确定支链氨基酸转氨酶 1 (BCAT1) 为 IFNγ 诱导的 CSC 可塑性的下游介质。体内靶向 BCAT1 通过防止 IFNγ 诱导的转移形成，改善了癌症疫苗接种和 ICB 治疗。接受 ICB 治疗的乳腺癌患者表现出类似的 CSC 标志物表达增加，表明对人类免疫激活的类似反应。总的来说，我们发现 IFNγ 具有出乎意料的促肿瘤作用，这可能导致癌症免疫治疗失败。
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