Nat Commun | 通过单细胞RNA-seq分析肝细胞癌中CTC的空间异质性和免疫逃避机制 (...
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Yun-Fan Sun , Liang Wu. et al.
Nat Commun, 2021.
In order to explore the key genes that promote the immune evasion ability of CTC, the research team analyzed the differential expression of immune evasion-related genes and cytokines in primary tumors and CTC. The results show that the immunosuppressive chemokine CCL5 ranks first in the up-regulated expression genes, and maintains a relatively high expression level during the process of CTC from HV to PA, PV and PoV. This finding was also verified by IF analysis. Through the analysis of published experimental data, the study found that the expression of CCL5 was positively correlated with Tregs (FOXP3) in HCC tumor tissue and PoV tumor thrombus, and the analysis of the TCGA data set confirmed that Treghigh/CCL5 CTChigh is the strongest early recurrence independent prognostic factors. In addition, the results of in vitro and in vivo models show that CTC can recruit Tregs through CCL5, thereby inhibiting the function of killer CD8 T cells, and establishing a local microenvironment conducive to their survival during the process of metastasis and colonization. The study used scRNA-seq to decipher the expression profile of CTCs and confirmed the spatial transcription heterogeneity and transfer mechanism between CTCs. Studies have found that CCL5is an important regulator of CTC immune evasion. The overexpression of CCL5 in CTC is regulated by the transcription of p38-MAX signal, which promotes immune escape and the transfer of CTCs by regulating Tregs. All in all, this study reveals the spatial heterogeneity and immune escape mechanism of primary livercancer, which is helpful for the design of new anti-metastatic treatment strategies.
doi: 10.1038/s41467-021-24386-0.
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Hong Zhang, Yuhui Xia, et al.
Advanced Science, 2021.
Epidemiological evidence indicates that alcoholism is one of the most important risk factors for colorectal cancer (CRC). Excessive drinking is associated with immunosuppression, which eliminates immune surveillance for tumor formation. According to reports, alcohol damages the function and activation of T cells and induces T cell apoptosis. However, the exact mechanism of alcohol-mediated T cell dysfunction to promote immune escape from CRC is still unclear. Programmed cell death receptor 1 (PD-1) is a key inhibitory receptor that resides on the surface of tumor-infiltrating lymphocytes (TILs). When combined with the main ligand PD-1 L1 expressed in tumor cells, it will promote T cells fail and inactivate the immune response. Anti-PD-1/anti-PD-1 L1 immune checkpoint blockade therapy disrupts the PD-1/PD-1L interaction by binding to inhibitory PD-1 receptors on TILs or PD-1 L1 of tumor cells , And reactivate anti-tumor Tcell-mediated cytotoxicity. In this study, alcohol was shown to induce PD-L1 expression in CRC cells. After alcohol exposure, mice with CRC tumors showed a higher response to anti-PD-1 treatment. It has also been found that drinking alcohol can induce the expression of ALDH2 in mice and tumor tissues of CRC patients. In addition, it was found that ALDH2 can promote the stability of PD-L1 protein. Importantly, the combination of ALDH2 inhibition and PD-1/PD-L1 checkpoint inhibitors has been shown to enhance the anti-tumor activity of effector immune cells. All in all, the results of the study show that drinking alcohol can induce ALDH2 and subsequently up-regulate the expression of PD-L1 in CRC, thereby protecting it from immune surveillance. In addition, the combination of ALDH2 inhibition and anti-PD-1 therapy can be used as a new strategy to enhance immune blocking therapy for CRC patients, especially alcoholic populations.
doi: 10.1002/advs.202003404.
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