ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.
ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.
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DOI：
10.1016/j.cell.2015.05.025
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发表时间：
2015-06-18
期刊：
影响因子：
64.5
通讯作者：
Glimcher LH
中科院分区：
文献类型：
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作者：
Cubillos-Ruiz JR;Silberman PC;Rutkowski MR;Chopra S;Perales-Puchalt A;Song M;Zhang S;Bettigole SE;Gupta D;Holcomb K;Ellenson LH;Caputo T;Lee AH;Conejo-Garcia JR;Glimcher LH
树突状细胞（DC）是启动和维持T细胞依赖性抗癌免疫所必需的。然而，肿瘤通常通过削弱正常DC功能来逃避免疫控制。内质网（ER）应激反应因子XBP1直接促进内在肿瘤生长，但它是否也调节宿主抗肿瘤免疫反应尚不清楚。在这里，我们表明，肿瘤相关DC（tDC）中的XBP1的组成性激活通过钝化抗肿瘤免疫来驱动卵巢癌（OvCa）的进展。由脂质过氧化副产物激发的XBP1活化诱导tDC中的甘油三酯生物合成程序，导致异常脂质积累和随后抑制tDC支持抗肿瘤T细胞的能力。因此，在tDC中DC特异性XBP1缺失或选择性纳米颗粒介导的XBP1沉默通过引起保护性1型抗肿瘤应答原位恢复其免疫刺激活性并延长存活。针对ER应激反应应该同时抑制肿瘤生长并增强抗癌免疫力，从而为癌症免疫治疗提供一种独特的方法。
Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.