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抵抗力，而且由活化的 T 细胞产生的干扰素γ (IFNγ) 直接将非 CSC 转化为 CSC。IFNγ 增强了几种 CSC 表型，例如对化疗和放疗的抵抗力以及转移形成。我们将支链氨基酸氨基转氨酶 1 (BCAT1) 鉴定为 IFNγ 诱导的 CSC 可塑性的下游介质。在体内靶向 BCAT1通过防止 IFNγ 诱导的转移形成，改进了癌症疫苗接种和 ICB 治疗。用 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反应相当。总的来说，我们发现 IFNγ 具有意想不到的促肿瘤作用，可能导致癌症免疫治疗失败。