Single-cell and spatial transcriptomic analysis reveals that an immune cell-related signature could predict clinical outcomes for microsatellite-stable colorectal cancer patients receiving immunotherapy.
- Author:
Shijin YUAN
1
;
Yan XIA
1
;
Guangwei DAI
1
;
Shun RAO
1
;
Rongrong HU
1
;
Yuzhen GAO
1
;
Qing QIU
1
;
Chenghao WU
1
;
Sai QIAO
1
;
Yinghua XU
2
;
Xinyou XIE
1
;
Haizhou LOU
2
;
Xian WANG
3
;
Jun ZHANG
4
Author Information
- Publication Type:Journal Article
- Keywords: Colorectal cancer (CRC); Immunotherapy; Microsatellite stability (MSS); Single-cell RNA sequencing (scRNA-seq); Spatial transcriptomics
- MeSH: Humans; Colorectal Neoplasms/drug therapy*; Male; Female; Immunotherapy; Middle Aged; Aged; Tumor Microenvironment/immunology*; Retrospective Studies; Microsatellite Instability; Transcriptome; Single-Cell Analysis; Programmed Cell Death 1 Receptor/immunology*; Gene Expression Profiling; Immune Checkpoint Inhibitors/therapeutic use*; Adult; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*
- From: Journal of Zhejiang University. Science. B 2025;26(4):371-392
- CountryChina
- Language:English
- Abstract: Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4+ T, regulatory CD4+ T, CD4+ Th17, exhausted CD8+ T, cytotoxic CD8+ T, proliferated CD8+ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
