Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.
Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.
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DOI：
10.1038/s41467-021-26407-4
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发表时间：
2021-10-28
影响因子：
16.6
通讯作者：
Hemann MT
中科院分区：
文献类型：
--
作者：
Bent EH;Millán-Barea LR;Zhuang I;Goulet DR;Fröse J;Hemann MT
细胞毒性化疗药物主要通过DNA损伤诱导的肿瘤细胞凋亡发挥作用，尽管这些药物引起的炎症可以刺激抗癌免疫应答。目前还不清楚控制这些不同效应和限制体内DNA损伤介导的细胞死亡的免疫原性应答的机制。使用BCR-ABL+ B细胞急性淋巴细胞白血病的小鼠模型，我们表明，化疗诱导的抗癌免疫抑制的肿瘤微环境，通过生产的细胞因子IL-6。化疗阿霉素通过诱导CD 8 + T细胞介导的抗癌反应在IL-6缺陷小鼠中具有治愈性，同时适度延长野生型荷瘤小鼠的寿命。我们还表明，IL-6抑制免疫检查点抑制与抗PD-L1阻断的有效性。我们的研究结果表明，IL-6是基因毒性应激诱导的抗癌免疫应答的关键调节因子，其抑制可以将癌细胞清除从主要的凋亡转变为免疫原性，促进和维持持久的抗肿瘤免疫应答。细胞毒性化疗很少产生持久的抗肿瘤免疫应答。在此，作者表明，肿瘤微环境来源的IL-6通过抑制B细胞急性淋巴细胞白血病临床前模型中的CD 8 T细胞抗肿瘤免疫应答来促进对阿霉素的耐药性。
Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses. Cytotoxic chemotherapy rarely generates durable anti-tumor immune responses. Here the authors show that tumor microenvironment-derived IL-6 promotes resistance to doxorubicin by suppressing CD8 T cell anti-tumor immune responses in a preclinical model of B-cell acute lymphoblastic leukemia.
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影响因子：
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作者：
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Agostinis P