Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer
Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer
复制标题
阻断缺氧诱导的骨髓细胞-1-阳性肿瘤相关巨噬细胞上表达的触发受体可逆转肝癌中的免疫抑制和抗程序性细胞死亡配体1抵抗
DOI：
10.1002/hep.30593
复制
发表时间：
2019-07-01
期刊：
影响因子：
13.5
通讯作者：
Zheng, Shusen
中科院分区：
文献类型：
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作者：
Wu, Qinchuan;Zhou, Wuhua;Zheng, Shusen
肿瘤相关巨噬细胞（tam）被认为是抗肿瘤抑制因子，但tam在肝细胞癌（HCC）缺氧环境中的行为尚不清楚。在这里，我们证明了缺氧诱导因子1 α诱导tam中髓系细胞上表达的触发受体-1 （TREM-1）的表达增加，导致免疫抑制。具体而言，TREM-1阳性（TREM-1(+)） tam在HCC进展晚期大量存在，间接损害CD8(+) T细胞的细胞毒功能，诱导CD8(+) T细胞凋亡。生物学和功能分析表明，TREM-1(+) tam在缺氧环境下具有较高的程序性细胞死亡配体1（PD-L1）表达。然而，TREM-1(+) tam可以在体内消除自发的和PD-L1阻断介导的抗肿瘤作用，这表明TREM-1(+) tam诱导的免疫抑制依赖于PD-L1/程序性细胞死亡1轴分离的途径。此外，TREM-1(+) tam相关的调节性T细胞（Tregs）对HCC抗pd - l1治疗的耐药性至关重要。机制上，TREM-1(+) tam通过细胞外信号调节的激酶/NF-kappa β途径提高趋化因子（C-C motif）配体20的表达，以响应缺氧和肿瘤代谢物，导致CCR6(+)Foxp3(+) Treg积累。阻断TREM-1通路可显著抑制肿瘤进展，减少CCR6(+)Foxp3(+) Treg募集，提高PD-L1阻断的治疗效果。因此，这些数据表明，在缺氧肿瘤环境下，CCR6(+)Foxp3(+) Treg募集对于TREM-1(+) tam介导的抗pd - l1耐药和免疫抑制至关重要。结论：本研究强调，缺氧环境通过TREM-1(+) tam吸引CCR6(+)Foxp3(+) Tregs引发肿瘤免疫抑制，TREM-1(+) tam赋予HCC抗pd - l1治疗抵抗。
Tumor-associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1 alpha induced increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, resulting in immunosuppression. Specifically, TREM-1-positive (TREM-1(+)) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8(+) T cells and induced CD8(+) T-cells apoptosis. Biological and functional assays showed that TREM-1(+) TAMs had higher expression of programmed cell death ligand 1 (PD-L1) under hypoxic environment. However, TREM-1(+) TAMs could abrogate spontaneous and PD-L1-blockade-mediated antitumor effects in vivo, suggesting that TREM-1(+) TAM-induced immunosuppression was dependent on a pathway separate from PD-L1/programmed cell death 1 axis. Moreover, TREM-1(+) TAM-associated regulatory T cells (Tregs) were crucial for HCC resistance to anti-PD-L1 therapy. Mechanistically, TREM-1(+) TAMs elevated chemokine (C-C motif) ligand 20 expression through the extracellular signal-regulated kinase/NF-kappa beta pathway in response to hypoxia and tumor metabolites leading to CCR6(+)Foxp3(+) Treg accumulation. Blocking the TREM-1 pathway could significantly inhibit tumor progression, reduce CCR6(+)Foxp3(+) Treg recruitment, and improve the therapeutic efficacy of PD-L1 blockade. Thus, these data demonstrated that CCR6(+)Foxp3(+) Treg recruitment was crucial for TREM-1(+) TAM-mediated anti-PD-L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM-1(+) TAMs attracting CCR6(+)Foxp3(+) Tregs, and TREM-1(+) TAMs endowed HCC with anti-PD-L1 therapy resistance.