Tang Yongchang, Wang Hong, Zhang Jiankun, Yang Chunhui, Xu Fei, Song Yan, Li Tianen, Zhang Qiangbo
Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, Shandong Province, China.
Department of Anesthesiology, Yidu Central Hospital, Weifang Medical University, Qingzhou, 262500, Shandong Province, China.
Sci Rep. 2025 Jan 20;15(1):2477. doi: 10.1038/s41598-025-86185-7.
The crosstalk between cancers and the immune microenvironment plays a critical role in malignant progression. FMS-like tyrosine kinase 3 (FLT3) is a frequently mutated gene in acute myeloid leukemia (AML). However, its role in solid cancers remains poorly understood. We analyzed the frequency of FLT3 alterations, its mRNA expression levels, and its prognostic implications across multiple cancer types. Additionally, we explored genes co-expressed with FLT3 and performed gene ontology analysis to identify associated biological processes. We also examined the relationship between FLT3 expression and markers of various immune cells, tertiary lymphoid structures (TLSs), and epithelial-mesenchymal transition. Furthermore, we validated these findings in our own cohort of hepatocellular carcinoma (HCC) patients. We found that FLT3 alteration and expression were both significantly upregulated in AML and were associated with poor prognosis, which is opposite to its role in solid cancers. The genes co-expressed with FLT3 in solid cancers were correlated with the regulation of the immune microenvironment. FLT3 was positively correlated with the formation of TLSs in only solid cancers, which was especially relevant to central memory T cells. We also found that FLT3 was positively correlated with the infiltration of NK cells, B cells, and DCs. It also positively correlated with the occurrence of apoptosis in solid cancers, but exhibited opposite roles in AML. The structural factors of the TLSs were positively correlated with FLT3 in solid cancers, but exhibited a negative correlation in AML. Meanwhile, we further validated the above conclusions in our own HCC cohort and demonstrated that FLT3 could serve as a predictive indicator of PD-1 treatment efficacy in HCC. In summary, the role of FLT3 is different in AML and solid cancers. FLT3 is associated with dendritic cell infiltration, tertiary lymphoid structure construction, and predict response to checkpoint inhibitors immunotherapy in HCC.
癌症与免疫微环境之间的相互作用在恶性进展中起着关键作用。FMS样酪氨酸激酶3（FLT3）是急性髓系白血病（AML）中常见的突变基因。然而，其在实体癌中的作用仍知之甚少。我们分析了多种癌症类型中FLT3改变的频率、其mRNA表达水平及其预后意义。此外，我们探索了与FLT3共表达的基因，并进行了基因本体分析以确定相关的生物学过程。我们还研究了FLT3表达与各种免疫细胞、三级淋巴结构（TLS）和上皮-间质转化标志物之间的关系。此外，我们在自己的肝细胞癌（HCC）患者队列中验证了这些发现。我们发现，FLT3改变和表达在AML中均显著上调，并与不良预后相关，这与其在实体癌中的作用相反。实体癌中与FLT3共表达的基因与免疫微环境的调节相关。FLT3仅在实体癌中与TLS的形成呈正相关，这与中央记忆T细胞尤其相关。我们还发现，FLT3与NK细胞、B细胞和DC的浸润呈正相关。它在实体癌中与细胞凋亡的发生也呈正相关，但在AML中表现出相反的作用。实体癌中TLS的结构因子与FLT3呈正相关，但在AML中呈负相关。同时，我们在自己的HCC队列中进一步验证了上述结论，并证明FLT3可作为HCC中PD-1治疗疗效的预测指标。总之，FLT3在AML和实体癌中的作用不同。FLT3与树突状细胞浸润、三级淋巴结构构建相关，并可预测HCC中检查点抑制剂免疫治疗的反应。
