IFNγ-induced stem-like state of cancer cells as a driver of metastatic progression following immunotherapy
IFNγ-induced stem-like state of cancer cells as a driver of metastatic progression following immunotherapy
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DOI：
10.1016/j.stem.2023.05.007
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发表时间：
2023-06-01
期刊：
影响因子：
23.9
通讯作者：
Huelsken, Joerg
中科院分区：
文献类型：
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作者：
Beziaud, Laurent;Young, C. Megan;Huelsken, Joerg
尽管免疫检查点阻断（ICB）治疗取得了显着的成功，但大多数癌症患者仍然没有反应。我们现在发现免疫疗法可以在肿瘤中诱导干细胞样特性。使用乳腺癌的小鼠模型，我们观察到癌症干细胞（CSC）不仅显示出对T细胞毒性的增强的抗性，而且由活化的T细胞产生的干扰素γ（IFN γ）直接将非CSC转化为CSC。IFN γ增强几种CSC表型，例如对化疗和放疗的抗性以及转移形成。我们确定了支链氨基酸氨基转氨酶1（BCAT1）作为IFN γ诱导的CSC可塑性的下游介质。体内靶向BCAT1通过防止IFN γ诱导的转移形成来改善癌症疫苗接种和ICB治疗。用ICB治疗的乳腺癌患者表现出CSC标志物表达的类似增加，表明对人类免疫激活的应答相当。总的来说，我们发现了IFN γ的一种意想不到的促肿瘤作用，可能导致癌症免疫治疗失败。
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 (IFNy) produced by activated T cells directly converts non-CSCs to CSCs. IFNy 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 IFNy-induced CSC plasticity. Targeting BCAT1 in vivo improved cancer vaccina-tion and ICB therapy by preventing IFNy-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 IFNy that may contribute to cancer immunotherapy failure.