Mitsuhashi Atsushi, Koyama Kazuya, Ogino Hirokazu, Afroj Tania, Nguyen Na Thi, Yoneda Hiroto, Otsuka Kenji, Sugimoto Masamichi, Kondoh Osamu, Nokihara Hiroshi, Hanibuchi Masaki, Takizawa Hiromitsu, Shinohara Tsutomu, Nishioka Yasuhiko
Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan.
Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, Kamakura 247-8530, Japan.
Cell Rep. 2023 Mar 28;42(3):112162. doi: 10.1016/j.celrep.2023.112162. Epub 2023 Mar 3.
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) antibody in vivo. Single-cell RNA sequencing of tumor-infiltrating CD45 cells identifies a distinct "fibrocyte cluster" from "macrophage clusters" in vivo and 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 CD45CD34 fibrocytes is enhanced by anti-PD-L1 antibody. Peritumoral implantation of fibrocytes enhances the antitumor effect of PD-L1 blockade in 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.
近期临床试验表明，免疫检查点抑制剂与抗血管生成药物联合治疗可改善多种癌症的预后。我们研究了纤维细胞（产生胶原蛋白的单核细胞衍生细胞）在联合免疫治疗中的作用。抗血管内皮生长因子（VEGF）抗体可增加肿瘤浸润性纤维细胞，并增强抗程序性死亡配体1（PD-L1）抗体在体内的抗肿瘤作用。对肿瘤浸润性CD45细胞进行单细胞RNA测序，可在体内及肺腺癌患者中区分出与“巨噬细胞簇”不同的“纤维细胞簇”。亚聚类分析揭示了一个高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性CD45⁺CD34⁻纤维细胞对CD8⁺T细胞的共刺激活性。在体内，瘤周植入纤维细胞可增强PD-L1阻断的抗肿瘤作用；而CD86⁺纤维细胞则无此作用。肿瘤浸润性纤维细胞通过转化生长因子β（TGF-β）/抗五聚体小体（SMAD）信号传导获得肌成纤维细胞样表型。因此，TGF-βR/SMAD抑制剂可通过调节纤维细胞分化增强VEGF和PD-L1双重阻断的抗肿瘤作用。纤维细胞被视为程序性死亡1（PD-1）/PD-L1阻断反应的调节因子。
