Cancer cell-intrinsic XBP1 mediates immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production. Cancer cell-intrinsic XBP1 mediates immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production

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 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 vesicle 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. Overall design: RNA-seq on subcutaneous MC38-OVA tumors in shNT and shXBP1 genotypes.

肿瘤组织中的敌对性微环境会破坏内质网稳态，并诱发未折叠蛋白反应（unfolded protein response, UPR）。癌细胞与肿瘤浸润白细胞中的慢性未折叠蛋白反应，可促进免疫监视逃逸。然而，癌细胞内的未折叠蛋白反应如何削弱抗肿瘤免疫应答，目前尚不明确。
本研究证实，在癌细胞中，未折叠蛋白反应组分X盒结合蛋白1（X-box binding protein 1, XBP1）可促进胆固醇的合成与分泌，该过程能够激活髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）并引发免疫抑制。胆固醇以小型细胞外囊泡（small extracellular vesicle）的形式被递送，并通过巨胞饮作用（macropinocytosis）被髓系来源抑制细胞摄取。
通过遗传学或药理学手段敲除XBP1，或降低肿瘤内胆固醇含量，可显著减少髓系来源抑制细胞的丰度，并触发强效的抗肿瘤应答。因此，本研究的数据揭示了XBP1/胆固醇信号通路在调控肿瘤生长中的细胞非自主作用，并提示抑制该通路可作为提升癌症免疫治疗疗效的有效策略。
整体实验设计：对shNT与shXBP1基因型小鼠的皮下MC38-OVA肿瘤开展RNA测序（RNA-seq）。