Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer.
Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer.
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抑制 BCL9 可调节结直肠癌肿瘤免疫微环境中肿瘤相关巨噬细胞的细胞景观
DOI：
10.3389/fphar.2021.713331
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zhu D
中科院分区：
文献类型：
--
作者：
Wei Z;Yang M;Feng M;Wu Z;Rosin-Arbesfeld R;Dong J;Zhu D
肿瘤相关巨噬细胞(TAMs)是肿瘤微环境(TME)中不可或缺的一部分，在肿瘤治疗中可能起到消极而非积极的作用。然而，在肿瘤基因失活或化学干扰的情况下，TAMS的细胞景观和转录谱调控仍不清楚。B细胞淋巴瘤9/B细胞淋巴瘤9样蛋白(BCL9/BCL9L)是β-连环蛋白的关键转录辅因子。抑制bcl9可抑制结直肠癌(CRC)小鼠模型的肿瘤生长。在这里，我们用单细胞测序的方法研究了结直肠癌的TAMS。Bcl9缺失导致巨噬细胞从M0到M2的极化抑制，并改变了CRC TME，从而进一步干扰了M0和M1的炎症。调控这些过程的转录因子可能从多个水平与Wnt信号通路有关。此外，我们还发现，在缺乏BCL9的人群中，从单核细胞到NK样无功能细胞的细胞明显不同。结合这些数据，我们提出了一种对NK细胞的评分来评估肿瘤基因组图谱临床标本中单核细胞/细胞和NK样非功能细胞TME的动态平衡，以验证其临床意义。我们证明了BCL9驱动的Wnt信号调控的TAMs的细胞类型平衡和转录差异影响了肿瘤的免疫监视和炎症，最终影响了患者的预后。因此，我们强调了通过肿瘤免疫治疗靶向Wnt信号通路的潜力。
Tumor-associated macrophages (TAMs) are an indispensable part of the tumor microenvironment (TME), and they likely play a negative rather than positive role in cancer treatment. However, the cellular landscape and transcriptional profile regulation of TAMs in the case of tumor gene inactivation or chemical interference remains unclear. The B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is a critical transcription co-factor of β-catenin. Suppression of Bcl9 inhibits tumor growth in mouse models of colorectal cancer (CRC). Here, we studied the TAMs of CRC by single-cell sequencing. Bcl9 depletion caused macrophage polarization inhibition from M0 to M2 and changed the CRC TME, which further interferes with the inflammation of M0 and M1. The transcription factor regulating these processes may be related to the Wnt signaling pathway from multiple levels. Furthermore, we also found that the cells delineated from monocyte to NK-like non-functioning cells were significantly different in the BCL9-deprived population. Combining these data, we proposed a TAM-to-NK score to evaluate the dynamic balance in TME of monocyte/TAM cells and NK-like non-functioning cells in The Cancer Genome Atlas (TCGA) clinical samples to verify the clinical significance. We demonstrated that the cell type balance and transcription differences of TAMs regulated by BCL9-driven Wnt signaling affected immune surveillance and inflammation of cancer, ultimately affecting patients’ prognosis. We thereby highlighted the potential of targeting Wnt signaling pathway through cancer immunotherapy.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
4.4
作者：
Bergenfelz, Caroline;Medrek, Catharina;Leandersson, Karin
通讯作者：
Leandersson, Karin
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
4.6
作者：
Maccio, Antonio;Gramignano, Giulia;Madeddu, Clelia
通讯作者：
Madeddu, Clelia
影响因子：
3.4
作者：
Fang, Yangyi;Kang, Yanhua;Zhang, Hang
通讯作者：
Zhang, Hang