He Ke-Jie, Gong Guoyu
The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou city, Zhejiang Province, China.
School of Medicine, Xiamen University, Xiamen, China.
BMC Gastroenterol. 2025 Mar 31;25(1):213. doi: 10.1186/s12876-025-03776-4.
This study aimed to decipher the intricate interplay between the immune landscape and CRC pathogenesis, elucidating how distinct immunophenotypes causally influence disease susceptibility and stratify patient outcomes.
We obtained the immunocyte phenotypes and CRC data from their respective genome-wide association studies. The primary analysis used the inverse variance weighting (IVW) method. We also simultaneously employed MR-Egger, weighted mode, simple mode, and weighted median approaches to strengthen the findings. Consensus clustering stratified 619 TCGA CRC patients by immunome expression. Functional assays examined the tumor suppressor GPD1L.
The IVW MR analysis identified 17 immunocyte phenotypes positively potentially associated with increased CRC risk (P < 0.05, OR > 1), and 18 phenotypes negatively potentially associated with decreased CRC risk (P < 0.05, OR < 1). These associations were not confounded by heterogeneity or horizontal pleiotropy (P > 0.05). Reverse MR analysis further revealed 4 additional immunocyte phenotypes positively potentially associated with CRC (P < 0.05, OR > 1). Clustering resolved prognostic C1/C2 subtypes dependent on coordinated immunophenotypic programs. GPD1L knockdown promoted CRC cell proliferation.
Genetic interrogation delineated causal immunome-CRC relationships at single-cell resolution. Immune-stratified CRC subtyping stratified patient outcomes. GPD1L exhibited tumor-suppressive functions. Our findings establish an integrated immunogenomic framework elucidating CRC pathogenesis with implications for precision immunotherapies.
本研究旨在解析免疫格局与结直肠癌发病机制之间的复杂相互作用，阐明不同的免疫表型如何因果性地影响疾病易感性并对患者预后进行分层。
我们从各自的全基因组关联研究中获取免疫细胞表型和结直肠癌数据。主要分析采用逆方差加权（IVW）方法。我们还同时采用了MR-Egger、加权模式、简单模式和加权中位数方法来强化研究结果。共识聚类根据免疫组表达对619例TCGA结直肠癌患者进行分层。功能实验检测了肿瘤抑制因子GPD1L。
IVW MR分析确定了17种免疫细胞表型与结直肠癌风险增加呈正相关（P < 0.05，OR > 1），以及18种表型与结直肠癌风险降低呈负相关（P < 0.05，OR < 1）。这些关联不受异质性或水平多效性的混淆（P > 0.05）。反向MR分析进一步揭示了另外4种与结直肠癌呈正相关的免疫细胞表型（P < 0.05，OR > 1）。聚类解析了依赖于协调免疫表型程序的预后C1/C2亚型。GPD1L基因敲低促进了结直肠癌细胞增殖。
基因分析在单细胞分辨率上描绘了因果性的免疫组-结直肠癌关系。免疫分层的结直肠癌亚型划分对患者预后进行了分层。GPD1L表现出肿瘤抑制功能。我们的研究结果建立了一个综合的免疫基因组框架，阐明了结直肠癌发病机制，对精准免疫治疗具有启示意义。
