Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer.
Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer.
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DOI：
10.1038/s41467-022-34428-w
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发表时间：
2022-11-04
影响因子：
16.6
通讯作者：
Fuchs, Serge Y.
中科院分区：
文献类型：
--
作者：
Lu, Zhen;Chen, Jinyun;Yu, Pengfei;Atherton, Matthew J.;Gui, Jun;Tomar, Vivek S.;Middleton, Justin D.;Sullivan, Neil T.;Singhal, Sunil;George, Subin S.;Woolfork, Ashley G.;Weljie, Aalim M.;Hai, Tsonwin;Eruslanov, Evgeniy B.;Fuchs, Serge Y.
呈递肿瘤抗原的树突状细胞（DC）的活性通常在肿瘤中受到抑制。在这里，我们报告这种抑制是由肿瘤微环境衍生因子诱导的，这些因子激活激活转录因子-3（ATF3）转录因子并下调胆固醇25-羟化酶（CH25H）。从人肺肿瘤中分离出的抗原呈递细胞中 CH25H 的缺失与肿瘤生长和肺癌进展相关。因此，DC 中缺乏 CH25H 的小鼠表现出肿瘤生长加速、浸润减少以及瘤内 CD8+ T 细胞活化受损。这些小鼠没有建立针对经历化疗诱导的免疫原性细胞死亡的恶性细胞的可测量的长期免疫力。从机制上讲，CH25H 的下调会刺激内噬体和溶酶体之间的膜融合，加速溶酶体降解并限制肿瘤抗原在瘤内 DC 中的交叉呈递。施用 STING 激动剂 MSA-2 可降低 DC 中的溶酶体活性，恢复抗原交叉呈递，并以 CH25H 依赖性方式提高 PD-1 阻断针对肿瘤攻击的治疗效果。这些研究强调了 DC 中 CH25H 下调对于肿瘤免疫逃避和治疗耐药的重要性。树突状细胞 (DC) 将肿瘤抗原呈递给 T 细胞，但这一过程在肿瘤微环境中存在缺陷。作者在这里发现胆固醇 25-羟化酶的下调是肿瘤抗原交叉呈递缺陷的基础。
Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8+ T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy. Dendritic cells (DC) present tumour antigens to T cells but this process is defective in the tumour microenvironment. Here the authors find that downregulation of cholesterol 25-hydroxylase underlies defective cross presentation of tumour antigens.
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影响因子：
64.5
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
通讯作者：
Glimcher LH
DOI：
10.1007/978-1-4939-8570-8_3
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Gibbings SL;Jakubzick CV
通讯作者：
Jakubzick CV
影响因子：
32.4
作者：
Bonavita E;Bromley CP;Jonsson G;Pelly VS;Sahoo S;Walwyn-Brown K;Mensurado S;Moeini A;Flanagan E;Bell CR;Chiang SC;Chikkanna-Gowda CP;Rogers N;Silva-Santos B;Jaillon S;Mantovani A;Reis e Sousa C;Guerra N;Davis DM;Zelenay S
通讯作者：
Zelenay S
影响因子：
18.4
作者：
Böttcher JP;Reis e Sousa C
通讯作者：
Reis e Sousa C
影响因子：
5.6
作者：
Chude CI;Amaravadi RK
通讯作者：
Amaravadi RK