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Transcriptome of CD8+ tumor-infiltrating T cells: a link between diabetes and colorectal cancer

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Abstract

There is an increased risk of colorectal cancer (CRC) development in patients with non-insulin-dependent type 2 diabetes. CD8+ T cells have been implicated in diabetes and are crucial for anti-tumor immunity. However, transcriptomic profiling for CD8+ T cells from CRC diabetic patients has not been explored. We performed RNA sequencing and compared transcriptomic profiles of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in CRC diabetic patients with CRC nondiabetic patients. We found that genes associated with ribogenesis, epigenetic regulations, oxidative phosphorylation and cell cycle arrest were upregulated in CD8+ TILs from diabetic patients, while genes associated with PI3K signaling pathway, cytokine response and response to lipids were downregulated. Among the significantly deregulated 1009 genes, 342 (186 upregulated and 156 downregulated) genes were selected based on their link to diabetes, and their associations with the presence of specific CRC pathological parameters were assessed using GDC TCGA colon database. The 186 upregulated genes were associated with the presence of colon polyps history (P = 0.0007) and lymphatic invasion (P = 0.0025). Moreover, CRC patients with high expression of the 186 genes were more likely to have poorer disease-specific survival (DSS) (Mantel–Cox log-rank P = 0.024) than those with low score. Our data provide novel insights into molecular pathways and biological functions, which could be altered in CD8+ TILs from CRC diabetic versus nondiabetic patients, and reveal candidate genes linked to diabetes, which could predict DSS and pathological parameters associated with CRC progression. However, further investigations using larger patient cohorts and functional studies are required to validate these findings.

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Data availability and material

The datasets used and/or analyzed during the current study are available from the corresponding author on request.

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Abbreviations

CD8+ TILs:

CD8+ Tumor-infiltrating lymphocytes

CRC:

Colorectal cancer

DAVID:

Database for annotation, visualization and integrated discovery

DEGs:

Differentially-expressed genes

DSS:

Disease-specific survival

GDC:

Genomic data commons

iDEP:

Integrated differential expression and pathway analysis

RNA-Seq:

RNA Sequencing

T2DM:

Type 2 diabetes mellitus

TCGA:

The cancer genome atlas

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Acknowledgements

We would like to thank the patients for donating their samples. This work was supported by a start-up Grant [VR04] for Professor Eyad Elkord from Qatar Biomedical research Institute, Qatar Foundation.

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Authors and Affiliations

  1. Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar

    Reem Saleh & Varun Sasidharan Nair

  2. Department of Pathology, Hamad Medical Corporation, Doha, Qatar

    Khaled Murshed

  3. Department of Surgery, Hamad Medical Corporation, Doha, Qatar

    Mohamed Abu Nada

  4. Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, M5 4WT, UK

    Eyad Elkord

  5. Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box: 34110, Doha, Qatar

    Ranad Shaheen

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  1. Reem Saleh
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Contributions

RS contributed to data curation, methodology, formal analysis, investigation and writing the original draft; VN contributed to data curation, methodology and formal analysis; KM and MAN contributed to sample acquisition and investigation; EE contributed to conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration, writing-review and editing; and RS contributed to conceptualization, data curation, formal analysis, validation, visualization, methodology, writing-review and editing.

Corresponding authors

Correspondence to Eyad Elkord or Ranad Shaheen.

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The authors declare no conflicts of interest.

Ethical approval

This study was executed under ethical approvals from Hamad Medical Corporation, Doha, Qatar (Protocol no. MRC-02-18-012) and Qatar Biomedical Research Institute, Doha, Qatar (Protocol no. 2017-006).

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The original online version of this article was revised: The gene names on Figure 3C in the proofs were missing.

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Saleh, R., Sasidharan Nair, V., Murshed, K. et al. Transcriptome of CD8+ tumor-infiltrating T cells: a link between diabetes and colorectal cancer. Cancer Immunol Immunother 70, 2625–2638 (2021). https://doi.org/10.1007/s00262-021-02879-7

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