Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
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DOI：
10.1016/j.cmet.2022.10.010
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发表时间：
2022-11
期刊：
影响因子：
29
通讯作者：
Zaili Yang;Yazhen Huo;Shixin Zhou;Jingya Guo;Xiaotu Ma;Tao Li;Congli Fan;Likun Wang
中科院分区：
文献类型：
--
作者：
Zaili Yang;Yazhen Huo;Shixin Zhou;Jingya Guo;Xiaotu Ma;Tao Li;Congli Fan;Likun Wang
肿瘤组织中的不利微环境破坏内质网稳态并诱导未折叠蛋白反应（UPR）。癌细胞和肿瘤浸润性白细胞中的慢性UPR可能有助于逃避免疫监视。然而，癌细胞中的UPR如何削弱抗肿瘤免疫反应尚不清楚。在这里，我们证明，在癌细胞中，UPR组分X-box结合蛋白1（XBP 1）有利于胆固醇的合成和分泌，从而激活骨髓源性抑制细胞（MDSC）并引起免疫抑制。胆固醇以小的细胞外囊泡的形式递送，并通过巨胞饮作用被MDSC内化。遗传或药理学上的XBP 1耗竭或降低肿瘤胆固醇含量显著降低MDSC丰度并引发强有力的抗肿瘤反应。因此，我们的数据揭示了XBP 1/胆固醇信号传导在调节肿瘤生长中的细胞非自主作用，并表明其抑制是提高癌症免疫疗法疗效的有用策略。
A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasis and induces the unfolded protein response (UPR). A chronic UPR in both cancer cells and tumor-infiltrating leukocytes could facilitate the evasion of immune surveillance. However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear. Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein 1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derived suppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered in the form of small extracellular vesicles and internalized by MDSCs through macropinocytosis. Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol content remarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus, our data unravel the cell-non-autonomous role of XBP1/cholesterol signaling in the regulation of tumor growth and suggest its inhibition as a useful strategy for improving the efficacy of cancer immunotherapy.