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Journal of Zhejiang University SCIENCE B 1998 Vol.-1 No.-1 P.

http://doi.org/10.1631/jzus.B2300679


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(s):  Shijin YUAN, Yan XIA, Guangwei DAI, Shun RAO, Rongrong HU, Yuzhen GAO, Qing QIU, Chenghao WU, Sai QIAO, Yinghua XU, Xinyou XIE, Haizhou LOU, Xian WANG, Jun ZHANG

Affiliation(s):  Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China; more

Corresponding email(s):   jameszhang2000@zju.edu.cn, wangx118@zju.edu.cn

Key Words:  Colorectal cancer, Microsatellite stable, Immunotherapy, Single-cell RNA sequencing, Spatial transcriptomics


Shijin YUAN, Yan XIA, Guangwei DAI, Shun RAO, Rongrong HU, Yuzhen GAO, Qing QIU, Chenghao WU, Sai QIAO, Yinghua XU, Xinyou XIE, Haizhou LOU, Xian WANG, Jun ZHANG. 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[J]. Journal of Zhejiang University Science B, 1998, -1(-1): .

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author="Shijin YUAN, Yan XIA, Guangwei DAI, Shun RAO, Rongrong HU, Yuzhen GAO, Qing QIU, Chenghao WU, Sai QIAO, Yinghua XU, Xinyou XIE, Haizhou LOU, Xian WANG, Jun ZHANG",
journal="Journal of Zhejiang University Science B",
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year="1998",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2300679"
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%A Shijin YUAN
%A Yan XIA
%A Guangwei DAI
%A Shun RAO
%A Rongrong HU
%A Yuzhen GAO
%A Qing QIU
%A Chenghao WU
%A Sai QIAO
%A Yinghua XU
%A Xinyou XIE
%A Haizhou LOU
%A Xian WANG
%A Jun ZHANG
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A1 - Shijin YUAN
A1 - Yan XIA
A1 - Guangwei DAI
A1 - Shun RAO
A1 - Rongrong HU
A1 - Yuzhen GAO
A1 - Qing QIU
A1 - Chenghao WU
A1 - Sai QIAO
A1 - Yinghua XU
A1 - Xinyou XIE
A1 - Haizhou LOU
A1 - Xian WANG
A1 - Jun ZHANG
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IS - -1
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B2300679


Abstract: 
Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) could enhance the anti-tumor activity of the 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 established 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) predicting the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared to VEGFRi alone, anti-PD-1 antibody and VEGFRi combination 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 similar adverse events incidence. Through single-cell and spatial transcriptomic analyses, we determined 10 MSS CRC-enriched immune cell types and their spatial distribution, including naïve CD4T, regulatory CD4T, Th17, exhausted CD8T, cytotoxic CD8T, proliferated CD8T, NK, plasma, and classical and intermediated monocytes. Based on a systemic meta-analysis and 10 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 receiving immunotherapy was also validated with the 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 with which to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.

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