Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy
Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy
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不完全射频消融引起的炎症加速肿瘤进展并阻碍PD-1免疫治疗
DOI：
10.1038/s41467-019-13204-3
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发表时间：
2019-11-28
影响因子：
16.6
通讯作者：
Liao, Weihua
中科院分区：
文献类型：
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作者：
Shi, Liangrong;Wang, Junjun;Liao, Weihua
射频消融(RFA)可促进肿瘤抗原特异性T细胞反应，增强临床前免疫治疗的效果。在此，我们报告了在结直肠癌肝转移(CRCLM)患者中，不完全射频消融(IRFA)后残留肿块的存在与较早的新转移和较低的存活率有关。利用小鼠模型，我们证明了IRFA促进了肿瘤的发展，并阻碍了抗PD-1治疗的效果。免疫分析表明，IRFA可诱导以髓系抑制细胞为主的持续局部炎症，抑制肿瘤中T细胞的功能。从机制上讲，肿瘤细胞来源的CCL2对单核细胞和肿瘤相关巨噬细胞(TAMs)的聚集至关重要。TAMs和肿瘤细胞之间的串扰增强了肿瘤细胞产生CCL2的能力。此外，我们发现，给予CCR2受体拮抗剂或在肿瘤细胞中失去CCL2表达可增强PD-1拮抗剂的抗肿瘤活性，为IRFA后残留肿瘤提供了一种挽救选择。
Radiofrequency ablation (RFA) promotes tumor antigen-specific T cell responses and enhances the effect of immunotherapy in preclinical settings. Here we report that the existence of remnant tumor masses due to incomplete RFA (iRFA) is associated with earlier new metastases and poor survival in patients with colorectal cancer liver metastases (CRCLM). Using mouse models, we demonstrate that iRFA promotes tumor progression and hinders the efficacy of anti-PD-1 therapy. Immune analysis reveals that iRFA induces sustained local inflammation with predominant myeloid suppressor cells, which inhibit T cell function in tumors. Mechanistically, tumor cell-derived CCL2 is critical for the accumulation of monocytes and tumor-associated macrophages (TAMs). The crosstalk between TAMs and tumor cells enhances the CCL2 production by tumor cells. Furthermore, we find that administration of a CCR2 antagonist or the loss of CCL2 expression in tumor cells enhances the antitumor activity of PD-1 blockade, providing a salvage alternative for residual tumors after iRFA.