Noh Sun Up, Lim Jinyeong, Shin Sung-Won, Kim Yeeun, Park Woong-Yang, Batinic-Haberle Ines, Choi Changhoon, Park Won
Department of Radiation Oncology, Samsung Medical Center, Seoul 06351, Republic of Korea.
Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
Antioxidants (Basel). 2024 Apr 17;13(4):477. doi: 10.3390/antiox13040477.
Manganese porphyrins reportedly exhibit synergic effects when combined with irradiation. However, an in-depth understanding of intratumoral heterogeneity and immune pathways, as affected by Mn porphyrins, remains limited. Here, we explored the mechanisms underlying immunomodulation of a clinical candidate, MnTnBuOE-2-PyP (BMX-001, MnBuOE), using single-cell analysis in a murine carcinoma model. Mice bearing 4T1 tumors were divided into four groups: control, MnBuOE, radiotherapy (RT), and combined MnBuOE and radiotherapy (MnBuOE/RT). In epithelial cells, the epithelial-mesenchymal transition, signaling via , angiogenesis, and hypoxia-related genes were significantly downregulated in the MnBuOE/RT group compared with the RT group. All subtypes of cancer-associated fibroblasts (CAFs) were clearly reduced in MnBuOE and MnBuOE/RT. Inhibitory receptor-ligand interactions, in which epithelial cells and CAFs interacted with CD8+ T cells, were significantly lower in the MnBuOE/RT group than in the RT group. Trajectory analysis showed that dendritic cells maturation-associated markers were increased in MnBuOE/RT. M1 macrophages were significantly increased in the MnBuOE/RT group compared with the RT group, whereas myeloid-derived suppressor cells were decreased. CellChat analysis showed that the number of cell-cell communications was the lowest in the MnBuOE/RT group. Our study is the first to provide evidence for the combined radiotherapy with a novel Mn porphyrin clinical candidate, BMX-001, from the perspective of each cell type within the tumor microenvironment.
据报道,锰卟啉与辐射联合使用时具有协同效应。然而,对于锰卟啉影响的肿瘤内异质性和免疫途径的深入了解仍然有限。在此,我们在小鼠癌模型中使用单细胞分析方法,探索了临床候选药物锰-四-(对-正丁氧基苯基)卟啉(BMX-001,MnBuOE)免疫调节的潜在机制。将携带4T1肿瘤的小鼠分为四组:对照组、MnBuOE组、放射治疗(RT)组以及MnBuOE与放射治疗联合组(MnBuOE/RT)。在上皮细胞中,与RT组相比,MnBuOE/RT组的上皮-间质转化、 信号通路、血管生成以及缺氧相关基因均显著下调。在MnBuOE组和MnBuOE/RT组中,所有亚型的癌症相关成纤维细胞(CAF)均明显减少。上皮细胞和CAF与CD8+ T细胞相互作用的抑制性受体-配体相互作用,在MnBuOE/RT组中显著低于RT组。轨迹分析表明,MnBuOE/RT组中树突状细胞成熟相关标志物增加。与RT组相比,MnBuOE/RT组中M1巨噬细胞显著增加,而骨髓来源的抑制性细胞减少。CellChat分析表明,MnBuOE/RT组中细胞间通讯的数量最少。我们的研究首次从肿瘤微环境中每种细胞类型的角度,为新型锰卟啉临床候选药物BMX-001联合放射治疗提供了证据。