Colorectal cancer–associated T cell receptor repertoire abnormalities are linked to gut microbiome shifts and somatic cell mutations

ABSTRACT

As with many diseases, tumor formation in colorectal cancer (CRC) is multifactorial and involves immune, environmental factors and various genetics that contribute to disease development. Accumulating evidence suggests that the gut microbiome is linked to the occurrence and development of CRC, and these microorganisms are important for immune maturation. However, a systematic perspective integrating microbial profiling, T cell receptor (TCR) and somatic mutations in humans with CRC is lacking. Here, we report distinct features of the expressed TCRβ repertoires in the peripheral blood of and CRC patients (n = 107) and healthy donors (n = 30). CRC patients have elevated numbers of large TCRβ clones and they have very low TCR diversity. The metagenomic sequencing data showed that the relative abundance of Fusobacterium nucleatum (F. nucleatum), Escherichia coli and Dasheen mosaic virus were elevated consistently in CRC patients (n = 97) compared to HC individuals (n = 30). The abundance of Faecalibacterium prausnitzii and Roseburia intestinalis was reduced in CRC (n = 97) compared to HC (n = 30). The correlation between somatic mutations of target genes (16 genes, n = 79) and TCR clonality and microbial biomarkers in CRC had been investigated. Importantly, we constructed a random forest classifier (contains 15 features) based on microbiome and TCR repertoires, which can be used as a clinical detection method to screen patients for CRC. We also analysis of F. nucleatum-specific TCR repertoire characteristics. Collectively, our large-cohort multi-omics data aimed to identify novel biomarkers to inform clinical decision-making in the detection and diagnosis of CRC, which is of possible etiological and diagnostic significance.

KEYWORDS:

• CRC
• TCR
• gut microbiota
• somatic mutations
• Fusobacterium nucleatum

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81802886) and Shanghai Tenth People’s Hospital Cultivation Project (2021SYPDRC029).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Yuan Cao designed the experiments, collected and process samples, analyzed the data and wrote the manuscript. Yanqiang Ding contributed greatly to the bioinformatics analysis section of the article. Jifeng Wang, Weiliang Hou, Yefei Zhu and Ruting Xie participated in the collection of samples. Jiayi Zheng and Zhan Cao participated in the analysis of the data. Qing Wei supervised the project. Huanlong Qin reviewed and edited the manuscript and supervised the project.

Data availability statement

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA002407) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2263934

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [81802886] and Climbing Talent Project of Shanghai Tenth People’s Hospital [2021SYPDRC029].