Wu Lei, Sun Shengnan, Qu Fei, Liu Xiuxiu, Sun Meili, Pan Ying, Zheng Yan, Su Guohai
Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
Research Center of Translational Medicine, Jinan Central Hospital, Shandong University, Jinan, China.
Front Immunol. 2022 Jun 3;13:829640. doi: 10.3389/fimmu.2022.829640. eCollection 2022.
Colon adenocarcinoma (COAD) is one of the leading causes of cancer-associated deaths worldwide. Patients with microsatellite instability-high (MSI-H) tumors were shown to highly benefit from immune checkpoint inhibitors (ICIs) than patients with microsatellite stable (MSS) tumors. Furthermore, the infiltration of immune cells and the expression of cancer stem cells (CSCs) in COAD were associated with the anti-tumor immune response. However, the potential mechanisms showing the relationship between microsatellite instability and CSCs or tumor-infiltrating immune cells (TIICs) have not been elucidated. Accumulating evidence reveals that achaete-scute family bHLH transcription factor 2 (ASCL2) plays a crucial role in the initiation and progression of COAD and drug resistance. However, the specific biological functions of ASCL2 in COAD remain unknown. In this study, we performed weighted gene co-expression network analysis (WGCNA) between MSS and MSI-H subsets of COAD. The results revealed that ASCL2 was a potential key candidate in COAD. Subsequently, the single-cell RNA-seq revealed that ASCL2 was positively associated with CSCs. Further, ASCL2 was shown to indirectly affect tumor immune cell infiltration by negatively regulating the expression of DUSP4. Finally, we inferred that the immunotherapy-sensitive role of ASCL2/DUSP4 axis on COAD is partly attributed to the activation of WNT/β-catenin pathway. In conclusion, this study revealed that ASCL2 was positively correlated to CSCs and tumor immune infiltration in COAD. Therefore, ASCL2 is a promising predictor of clinical responsiveness to anti-PD-1/PD-L1 therapy in COAD.
结肠癌（COAD）是全球癌症相关死亡的主要原因之一。研究表明，与微卫星稳定（MSS）肿瘤患者相比，微卫星高度不稳定（MSI-H）肿瘤患者从免疫检查点抑制剂（ICI）中获益更多。此外，COAD中免疫细胞的浸润以及癌症干细胞（CSC）的表达与抗肿瘤免疫反应相关。然而，微卫星不稳定性与CSC或肿瘤浸润免疫细胞（TIIC）之间关系的潜在机制尚未阐明。越来越多的证据表明，无翅型MMTV整合位点家族bHLH转录因子2（ASCL2）在COAD的发生、发展及耐药中起关键作用。然而，ASCL2在COAD中的具体生物学功能仍不清楚。在本研究中，我们对COAD的MSS和MSI-H亚组进行了加权基因共表达网络分析（WGCNA）。结果显示，ASCL2是COAD中一个潜在的关键候选基因。随后，单细胞RNA测序显示ASCL2与CSC呈正相关。此外，ASCL2通过负调控双特异性磷酸酶4（DUSP4）的表达间接影响肿瘤免疫细胞浸润。最后，我们推断ASCL2/DUSP4轴对COAD的免疫治疗敏感性作用部分归因于WNT/β-连环蛋白通路的激活。总之，本研究表明ASCL2与COAD中的CSC和肿瘤免疫浸润呈正相关。因此，ASCL2是COAD中抗PD-1/PD-L1治疗临床反应性的一个有前景的预测指标。
