A conserved dendritic-cell regulatory program limits antitumour immunity.
A conserved dendritic-cell regulatory program limits antitumour immunity.
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DOI：
10.1038/s41586-020-2134-y
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发表时间：
2020-04
期刊：
影响因子：
64.8
通讯作者：
Merad M
中科院分区：
文献类型：
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作者：
Maier B;Leader AM;Chen ST;Tung N;Chang C;LeBerichel J;Chudnovskiy A;Maskey S;Walker L;Finnigan JP;Kirkling ME;Reizis B;Ghosh S;D'Amore NR;Bhardwaj N;Rothlin CV;Wolf A;Flores R;Marron T;Rahman AH;Kenigsberg E;Brown BD;Merad M
检查点阻断疗法改善了癌症治疗，但这种免疫治疗方案在很大一部分患者中失败。在临床前模型中，传统的1型树突状细胞（DC1s）控制着对检查点阻断的反应，并与癌症患者更好的总生存率相关，这反映了这些细胞启动CD8+ T细胞反应的特殊能力。然而，矛盾的是，可以在抵抗检查点封锁的肿瘤中发现DC1s，这表明这些细胞的功能可能在某些病变中被改变。在这里，我们在人类和小鼠非小细胞肺癌中使用单细胞RNA测序，鉴定了一组树突状细胞（dc），我们将其命名为“富含免疫调节分子的成熟dc”（mregdc），因为它们共同表达免疫调节基因（Cd274、Pdcd1lg2和Cd200）和成熟基因（Cd40、Ccr7和Il12b）。我们发现mregDC程序在摄取肿瘤抗原后由典型的DC1s和DC2s表达。我们进一步发现mregdc中程序性死亡配体1蛋白（一个关键检查点分子）的上调是由受体酪氨酸激酶AXL诱导的，而白细胞介素(IL)-12的上调则严格依赖于干扰素-？并受IL-4信号负向控制。阻断IL-4可增强携带肿瘤抗原的mregDC1s产生IL-12，扩大肿瘤浸润效应T细胞的数量，减轻肿瘤负担。因此，我们发现了一个与肿瘤抗原摄取相关的调节模块，可以降低人类和小鼠癌症中的DC1功能。
Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8+ T cells. Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name ‘mature DCs enriched in immunoregulatory molecules’ (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein–a key checkpoint molecule–in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-? and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.
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DOI：
10.1126/science.1247651
发表时间：
2014-02-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jaitin DA;Kenigsberg E;Keren-Shaul H;Elefant N;Paul F;Zaretsky I;Mildner A;Cohen N;Jung S;Tanay A;Amit I
通讯作者：
Amit I
影响因子：
48
作者：
Stoeckius M;Hafemeister C;Stephenson W;Houck-Loomis B;Chattopadhyay PK;Swerdlow H;Satija R;Smibert P
通讯作者：
Smibert P
影响因子：
15.9
作者：
Helft, Julie;Manicassamy, Balaji;Merad, Miriam
通讯作者：
Merad, Miriam
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS
DOI：
10.1158/1078-0432.ccr-16-2586
发表时间：
2017-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Skinner HD;Giri U;Yang LP;Kumar M;Liu Y;Story MD;Pickering CR;Byers LA;Williams MD;Wang J;Shen L;Yoo SY;Fan YH;Molkentine DP;Beadle BM;Meyn RE;Myers JN;Heymach JV
通讯作者：
Heymach JV