小柯机器人

保守DC调控限制抗肿瘤免疫力
2020-03-30 15:37

美国纽约州西奈山伊坎医学院Miriam Merad及其研究组发现,保守的树突状细胞(DC)调控程序限制了抗肿瘤免疫力。该项研究成果发表在2020325日出版的《自然》杂志上。

他们在人和小鼠非小细胞肺癌中进行单细胞RNA测序,鉴定了一群DC,并将其命名为富含免疫调节分子的成熟DC”mregDC),这是由于它们共表达了免疫调节基因(Cd274Pdcd1lg2Cd200)和成熟基因(Cd40Ccr7Il12b)。

他们发现,mregDC程序由摄取肿瘤抗原后的传统1型树突状细胞(DC1s)和DC2表达。他们进一步发现,受体酪氨酸激酶AXL诱导mregDCs中的程序性死亡配体1蛋白(关键的检验点分子)上调,而白介素(IL-12的上调严格依赖于干扰素,并由IL-4信号负调控。

阻断IL-4可通过携带肿瘤抗原的mregDC1s促进IL-12的产生,扩大肿瘤浸润的效应T细胞库并减少肿瘤负荷。因此,他们发现了与肿瘤抗原摄取相关的调控模块,该模块降低了人类和小鼠癌症中的DC1功能。

据了解,检验点阻断疗法改善了癌症的治疗,但是这种免疫疗法在大部分患者中均无效。传统的DC1s在临床前模型中控制对检验站阻断的反应,并与癌症患者更好的总体生存率相关,反映了这些细胞对CD8 + T细胞反应的特化能力。然而,自相矛盾的是,DC1s可以在抵抗检验点阻断的肿瘤中发现,表明这些细胞的功能可能在某些病变中发生了改变。

附:英文原文

Title: A conserved dendritic-cell regulatory program limits antitumour immunity

Author: Barbara Maier, Andrew M. Leader, Steven T. Chen, Navpreet Tung, Christie Chang, Jessica LeBerichel, Aleksey Chudnovskiy, Shrisha Maskey, Laura Walker, John P. Finnigan, Margaret E. Kirkling, Boris Reizis, Sourav Ghosh, Natalie Roy DAmore, Nina Bhardwaj, Carla V. Rothlin, Andrea Wolf, Raja Flores, Thomas Marron, Adeeb H. Rahman, Ephraim Kenigsberg, Brian D. Brown, Miriam Merad

Issue&Volume: 2020-03-25

Abstract: 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 cells1,2,3. 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-γ 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.

DOI: 10.1038/s41586-020-2134-y

Source: https://www.nature.com/articles/s41586-020-2134-y

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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