Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Nat Cancer. 2021 Apr;2(4):457-473. doi: 10.1038/s43018-021-00196-7. Epub 2021 Apr 12.
Although chemotherapy can stimulate antitumor immunity by inducing interferon (IFN) response, the functional role of tumor-associated macrophages in this scenario remains unclear. Here, we found that IFN-activated proinflammatory macrophages after neoadjuvant chemotherapy enhanced antitumor immunity but promoted cancer chemoresistance. Mechanistically, IFN induced expression of cytoplasmic long noncoding RNA IFN-responsive nuclear factor-κB activator (IRENA) in macrophages, which triggered nuclear factor-κB signaling via dimerizing protein kinase R and subsequently increased production of protumor inflammatory cytokines. By constructing macrophage-conditional IRENA-knockout mice, we found that targeting IRENA in IFN-activated macrophages abrogated their protumor effects, while retaining their capacity to enhance antitumor immunity. Clinically, IRENA expression in post-chemotherapy macrophages was associated with poor patient survival. These findings indicate that lncRNA can determine the dichotomy of inflammatory cells on cancer progression and antitumor immunity and suggest that targeting IRENA is an effective therapeutic strategy to reversing tumor-promoting inflammation.
虽然化疗通过诱导干扰素（IFN）反应可以刺激抗肿瘤免疫，但肿瘤相关巨噬细胞在这种情况下的功能作用尚不清楚。在这里，我们发现新辅助化疗后 IFN 激活的促炎巨噬细胞增强了抗肿瘤免疫，但促进了癌症的化疗耐药性。在机制上，IFN 在巨噬细胞中诱导细胞质长非编码 RNA IFN 反应性核因子-κB 激活物（IRENA）的表达，通过二聚蛋白激酶 R 触发核因子-κB 信号通路，进而增加促肿瘤炎症细胞因子的产生。通过构建巨噬细胞条件性 IRENA 敲除小鼠，我们发现靶向 IFN 激活巨噬细胞中的 IRENA 可消除其促肿瘤作用，同时保留其增强抗肿瘤免疫的能力。临床上，化疗后巨噬细胞中的 IRENA 表达与患者生存不良相关。这些发现表明，lncRNA 可以决定炎症细胞在癌症进展和抗肿瘤免疫中的双重作用，并表明靶向 IRENA 是一种有效的治疗策略，可以逆转促进肿瘤的炎症。
