Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
Agora Cancer Research Center, Lausanne, Switzerland.
Nat Cancer. 2024 Feb;5(2):240-261. doi: 10.1038/s43018-023-00668-y. Epub 2023 Nov 23.
Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8 T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.
树突状细胞 (DCs) 是一种呈递抗原的髓样细胞，可调节 T 细胞的激活、迁移和功能。用肿瘤抗原脉冲处理的单核细胞来源的树突状细胞已在癌症的治疗性疫苗接种中进行了广泛测试，但其临床结果喜忧参半。在这里，我们提出了一种基于小鼠或人树突状细胞前体细胞 (DCP) 的细胞治疗平台，这些细胞经过工程改造后可产生两种免疫刺激细胞因子，IL-12 和 FLT3L。细胞因子武装的 DCP 分化为传统的 I 型树突状细胞 (cDC1)，可抑制肿瘤生长，包括黑色素瘤和同源性肝模型，而无需抗原加载或骨髓清除性宿主调理。肿瘤反应涉及 IL-12 和 FLT3L 的协同作用，与自然杀伤细胞和 T 细胞浸润和激活、M1 样巨噬细胞编程和缺血性肿瘤坏死有关。抗肿瘤免疫依赖于内源性 cDC1 的扩增和干扰素-γ 信号，但不依赖于 CD8 T 细胞的细胞毒性。细胞因子武装的 DCP 与抗 GD2 嵌合抗原受体 (CAR) T 细胞在小鼠中协同有效地根除颅内神经胶质瘤，说明了它们在联合治疗中的潜力。
