CD169-positive macrophages enhance abscopal effect of radiofrequency ablation therapy in liver cancer
CD169-positive macrophages enhance abscopal effect of radiofrequency ablation therapy in liver cancer
复制标题
CD169阳性巨噬细胞增强肝癌射频消融治疗的远隔效应
DOI：
10.1016/j.tranon.2021.101306
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发表时间：
2022-01-01
影响因子：
5
通讯作者：
Ma，Chunhong
中科院分区：
文献类型：
--
作者：
Song，Xiaojia;Li，Na;Ma，Chunhong
射频消融术(RFA)是一种应用广泛且有效的治疗小病灶的原发性或转移性肝癌的方法。然而，RFA在控制转移或复发方面的疗效仍然有限。巨噬细胞是肿瘤微环境(TME)中的主要细胞群，已有报道称巨噬细胞被募集到RFA治疗的病灶中，但其作用尚不清楚。在这里，我们成功地建立了模拟RFA诱导的异位效应的小鼠模型，在该模型中，RFA消除了局部原位肝肿瘤，但无法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)的前列腺癌激活，但未能重新编程远距离的TAM。重要的是，尽管RFA导致局部CD169+巨噬细胞比例降低，免疫抑制分子TIM-3和PD-L1的表达减少，但远端TME中CD169+巨噬细胞没有观察到这些变化。进一步的RNA-SEQ和流式细胞术分析表明，肝CD169+巨噬细胞通过募集CD8+T/NK细胞和抑制MDSCs/Tregs的积聚而参与TME的再编程。在CD169-DTR小鼠中，CD169+巨噬细胞的耗尽一直极大地促进了肝癌的进展，并在很大程度上抑制了RFA诱导的肿瘤抑制。值得注意的是，CD169+巨噬细胞的转移协同增强了RFA诱导的对远处肿瘤的抑制。据我们所知，这是第一个证明肝脏CD169+巨噬细胞是RFA诱导的非局域效应的关键因素的研究。我们的数据表明，转移CD169+巨噬细胞的RFA是一种有希望的联合治疗方法，可以减少肝癌患者的转移或复发。
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.