Immunosuppressive Microenvironment Revealed by Immune Cell Landscape in Pre-metastatic Liver of Colorectal Cancer.
Immunosuppressive Microenvironment Revealed by Immune Cell Landscape in Pre-metastatic Liver of Colorectal Cancer.
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结直肠癌转移前肝脏中免疫细胞景观揭示的免疫抑制微环境。
DOI：
10.3389/fonc.2021.620688
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发表时间：
2021
影响因子：
4.7
通讯作者：
Liao W
中科院分区：
文献类型：
--
作者：
Zeng D;Wang M;Wu J;Lin S;Ye Z;Zhou R;Wang G;Wu J;Sun H;Bin J;Liao Y;Li N;Shi M;Liao W
背景：结直肠癌是癌症死亡率的第四大原因，易于转移，尤其是转移到肝脏。包括各种驻留基质细胞和免疫细胞的转移前微环境对于转移是必需的。然而，免疫组分的动态演变如何促进转移前小生境的形成仍不清楚。研究方法：利用来自我们的原位结直肠癌小鼠模型的RNA-seq数据，我们应用单样本基因集富集分析和通过估计RNA转录物的相对子集来鉴定细胞类型，以研究转移前肝脏的肿瘤微环境景观，并确定髓源性抑制细胞（MDSC）在浸润免疫细胞和基因通路激活调节中的确切作用。进行流式细胞术分析以定量人和小鼠样品中的MDSC水平。结果如下：在目前的工作中，基于高通量转录组数据，我们描绘了转移前肝脏的免疫细胞浸润模式，并强调MDSC是主要的改变细胞类型。值得注意的是，流式细胞术分析显示，在原位结直肠癌荷瘤小鼠的转移前肝脏和I-III期结直肠癌患者的外周血中检测到高频率的MDSC。MDSC在肝脏中的积累驱动免疫抑制因子分泌和免疫检查点评分上调，从而形成具有持续免疫抑制的转移前小生境。原发性肿瘤中的代谢重编程（如上调的糖酵解/糖异生和HIF-1信号通路）也被证明与转移前肝脏中的MDSC浸润相关。一些趋化因子被鉴定为MDSC募集的潜在机制。结论：总的来说，我们的研究阐明了MDSC在转移前小生境转化过程中的变化，并阐明了原发性肿瘤影响MDSC在靶向肝脏中聚集的潜在生物学机制。
Background: Colorectal cancer, the fourth leading cause of cancer mortality, is prone to metastasis, especially to the liver. The pre-metastatic microenvironment comprising various resident stromal cells and immune cells is essential for metastasis. However, how the dynamic evolution of immune components facilitates pre-metastatic niche formation remains unclear. Methods: Utilizing RNA-seq data from our orthotopic colorectal cancer mouse model, we applied single sample gene set enrichment analysis and Cell type Identification By Estimating Relative Subsets Of RNA Transcripts to investigate the tumor microenvironment landscape of pre-metastatic liver, and define the exact role of myeloid-derived suppressor cells (MDSCs) acting in the regulation of infiltrating immune cells and gene pathways activation. Flow cytometry analysis was conducted to quantify the MDSCs levels in human and mice samples. Results: In the current work, based on the high-throughput transcriptome data, we depicted the immune cell infiltration pattern of pre-metastatic liver and highlighted MDSCs as the dominant altered cell type. Notably, flow cytometry analysis showed that high frequencies of MDSCs, was detected in the pre-metastatic liver of orthotopic colorectal cancer tumor-bearing mice, and in the peripheral blood of patients with stage I–III colorectal cancer. MDSCs accumulation in the liver drove immunosuppressive factors secretion and immune checkpoint score upregulation, consequently shaping the pre-metastatic niche with sustained immune suppression. Metabolic reprogramming such as upregulated glycolysis/gluconeogenesis and HIF-1 signaling pathways in the primary tumor was also demonstrated to correlate with MDSCs infiltration in the pre-metastatic liver. Some chemokines were identified as a potential mechanism for MDSCs recruitment. Conclusion: Collectively, our study elucidates the alterations of MDSCs during pre-metastatic niche transformation, and illuminates the latent biological mechanism by which primary tumors impact MDSC aggregation in the targeted liver.
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影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
2.1
作者：
Ghasemi A;Zahediasl S
通讯作者：
Zahediasl S
影响因子：
3.4
作者：
Liu, Wei;Hou, Yufang;Jiang, Ying
通讯作者：
Jiang, Ying
影响因子：
6.6
作者：
Angell, Trevor E.;Lechner, Melissa G.;Epstein, Alan L.
通讯作者：
Epstein, Alan L.
影响因子：
82.9
作者：
Auslander N;Zhang G;Lee JS;Frederick DT;Miao B;Moll T;Tian T;Wei Z;Madan S;Sullivan RJ;Boland G;Flaherty K;Herlyn M;Ruppin E
通讯作者：
Ruppin E