Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade
Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade
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DOI：
10.1016/j.celrep.2023.112162
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发表时间：
2023-03-28
期刊：
影响因子：
8.8
通讯作者：
Nishioka，Yasuhiko
中科院分区：
文献类型：
--
作者：
Mitsuhashi，Atsushi;Koyama，Kazuya;Nishioka，Yasuhiko
最近的临床试验表明，免疫检查点抑制剂和抗血管生成试剂联合治疗可以改善各种癌症的预后。我们研究了纤维细胞（产生胶原的单核细胞衍生细胞）在联合免疫疗法中的作用。抗 VEGF（血管内皮生长因子）抗体可增加肿瘤浸润纤维细胞，并增强抗 PD-L1（程序性死亡配体 1）抗体的体内抗肿瘤作用。对肿瘤浸润 CD45+ 细胞进行单细胞 RNA 测序，在体内和肺腺癌患者中识别出与“巨噬细胞簇”不同的“纤维细胞簇”。亚聚类分析揭示了高度表达共刺激分子的纤维细胞亚簇。抗 PD-L1 抗体可增强肿瘤浸润 CD45+CD34+ 纤维细胞的 CD8+T 细胞共刺激活性。纤维细胞的瘤周植入可增强体内 PD-L1 阻断的抗肿瘤作用； CD86−/−纤维细胞则不然。肿瘤浸润纤维细胞通过转化生长因子 β (TGF-β)/小母体对抗十肢瘫痪 (SMAD) 信号获得肌成纤维细胞样表型。因此，TGF-βR/SMAD抑制剂通过调节纤维细胞分化来增强VEGF和PD-L1双重阻断的抗肿瘤作用。纤维细胞被强调为程序性死亡 1 (PD-1)/PD-L1 阻断反应的调节因子。
Recent clinical trials revealed that immune checkpoint inhibitors and antiangiogenic reagent combination therapy improved the prognosis of various cancers. We investigated the roles of fibrocytes, collagen-producing monocyte-derived cells, in combination immunotherapy. Anti-VEGF (vascular endothelial growth factor) antibody increases tumor-infiltrating fibrocytes and enhances the antitumor effects of anti-PD-L1 (programmed death ligand 1) antibodyin vivo. Single-cell RNA sequencing of tumor-infiltrating CD45+cells identifies a distinct "fibrocyte cluster" from "macrophage clusters"in vivoand in lung adenocarcinoma patients. A sub-clustering analysis reveals a fibrocyte sub-cluster that highly expresses co-stimulatory molecules. CD8+T cell-costimulatory activity of tumor-infiltrating CD45+CD34+fibrocytes is enhanced by anti-PD-L1 antibody. Peritumoral implantation of fibrocytes enhances the antitumor effect of PD-L1 blockadein vivo; CD86−/−fibrocytes do not. Tumor-infiltrating fibrocytes acquire myofibroblast-like phenotypes through transforming growth factor β (TGF-β)/small mothers against decapentaplegic (SMAD) signaling. Thus, TGF-βR/SMAD inhibitor enhances the antitumor effects of dual VEGF and PD-L1 blockade by regulating fibrocyte differentiation. Fibrocytes are highlighted as regulators of the response to programmed death 1 (PD-1)/PD-L1 blockade.