保守DC調控限制抗腫瘤免疫力
作者：
小柯機器人發布時間：2020/3/30 15:37:13
美國紐約州西奈山伊坎醫學院Miriam Merad及其研究組發現，保守的樹突狀細胞（DC）調控程序限制了抗腫瘤免疫力。該項研究成果發表在2020年3月25日出版的《自然》雜誌上。
他們在人和小鼠非小細胞肺癌中進行單細胞RNA測序，鑑定了一群DC，並將其命名為「富含免疫調節分子的成熟DC」（mregDC），這是由於它們共表達了免疫調節基因（Cd274，Pdcd1lg2和Cd200）和成熟基因（Cd40，Ccr7和Il12b）。
他們發現，mregDC程序由攝取腫瘤抗原後的傳統1型樹突狀細胞（DC1s）和DC2表達。他們進一步發現，受體酪氨酸激酶AXL誘導mregDCs中的程序性死亡配體1蛋白（關鍵的檢驗點分子）上調，而白介素（IL）-12的上調嚴格依賴於幹擾素-γ，並由IL-4信號負調控。
阻斷IL-4可通過攜帶腫瘤抗原的mregDC1s促進IL-12的產生，擴大腫瘤浸潤的效應T細胞庫並減少腫瘤負荷。因此，他們發現了與腫瘤抗原攝取相關的調控模塊，該模塊降低了人類和小鼠癌症中的DC1功能。
據了解，檢驗點阻斷療法改善了癌症的治療，但是這種免疫療法在大部分患者中均無效。傳統的DC1s在臨床前模型中控制對檢驗站阻斷的反應，並與癌症患者更好的總體生存率相關，反映了這些細胞對CD8 + T細胞反應的特化能力。然而，自相矛盾的是，DC1s可以在抵抗檢驗點阻斷的腫瘤中發現，表明這些細胞的功能可能在某些病變中發生了改變。
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