Song Xiaojia, Li Na, Liu Yuan, Wang Zehua, Wang Tixiao, Tan Siyu, Li Chunyang, Qiu Chunhong, Gao Lifen, Asano Kenichi, Tanaka Masato, Liang Xiaohong, Liu Xinyong, Ma Chunhong
Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China; Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province, and Department of Immunology, School of Basic Medical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province, and Department of Immunology, School of Basic Medical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
Transl Oncol. 2022 Jan;15(1):101306. doi: 10.1016/j.tranon.2021.101306. Epub 2021 Dec 6.
Radiofrequency ablation (RFA) is a widely used and effective treatment for primary or metastatic liver cancer with small-size lesions. However, the therapeutic effectiveness of RFA in controlling metastatic lesion or recurrence is still limited. As the major cell population in tumor microenvironment (TME), macrophages have been reported to be recruited to RFA-treated lesion, but their roles are still unclear. Herein, we successfully established the mouse model mimicking RFA-induced abscopal effect, in which RFA eliminated the local orthotopic liver tumor but failed to control growth of distant tumor. Correspondently, RFA suppressed protumoral activation of local tumor-associated macrophages (TAMs), but failed to reprogram TAMs in distance. Importantly, although RFA led to reduced proportion of hepatic CD169 macrophages in local and decreased expression of immune inhibitory molecules Tim-3 and PD-L1, these alterations were not observed for CD169 macrophages in distant TME. Further RNA-seq and flow cytometry analysis showed that hepatic CD169 macrophages contributed to reprograming TME through recruiting CD8 T/NK cells and suppressing accumulation of MDSCs/Tregs. Consistently, depletion of CD169 macrophages in CD169-DTR mouse greatly promoted liver tumor progression and largely dampened RFA-induced tumor suppression. Notably, transfer of CD169 macrophages synergistically enhanced RFA-induced inhibition of distant tumor. To our knowledge, this is the first study which demonstrates hepatic CD169 macrophages as a key factor responsible for RFA-induced abscopal effect. Our data suggest RFA with transfer of CD169 macrophages as a promising combination therapy to lessen metastasis or recurrence of liver cancer in patients.
射频消融（RFA）是一种广泛应用且有效的治疗原发性或转移性小病灶肝癌的方法。然而，RFA在控制转移病灶或复发方面的治疗效果仍然有限。巨噬细胞作为肿瘤微环境（TME）中的主要细胞群体，已被报道可被募集至RFA治疗的病灶处，但其作用仍不明确。在此，我们成功建立了模拟RFA诱导的远隔效应的小鼠模型，其中RFA消除了局部原位肝肿瘤，但未能控制远处肿瘤的生长。相应地，RFA抑制了局部肿瘤相关巨噬细胞（TAM）的促肿瘤激活，但未能对远处的TAM进行重编程。重要的是，尽管RFA导致局部肝脏CD169巨噬细胞比例降低以及免疫抑制分子Tim-3和PD-L1的表达减少，但在远处TME中的CD169巨噬细胞未观察到这些改变。进一步的RNA测序和流式细胞术分析表明，肝脏CD169巨噬细胞通过募集CD8 T/NK细胞和抑制MDSCs/Tregs的积累来促进TME的重编程。一致地，在CD169-DTR小鼠中耗尽CD169巨噬细胞极大地促进了肝肿瘤进展，并在很大程度上削弱了RFA诱导的肿瘤抑制作用。值得注意的是，转移CD169巨噬细胞协同增强了RFA诱导的对远处肿瘤的抑制作用。据我们所知，这是第一项证明肝脏CD169巨噬细胞是RFA诱导的远隔效应的关键因素的研究。我们的数据表明，RFA联合转移CD169巨噬细胞是一种有前景的联合治疗方法，可减少肝癌患者的转移或复发。
