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Interleukin-38 in colorectal cancer: a potential role in precision medicine

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Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related death, partly due to a lack of reliable biomarkers for early diagnosis. To improve the outcome of CRC, it is critical to provide diagnosis at an early stage using promising sensitive/specific marker(s). Using immunohistochemistry and histopathology, IL-38 expression was determined in tissue arrays of CRC with different TNM status and depth of tumour invasion. Data were compared to IL-38 in adjacent non-cancer tissue and correlated with demographic information, including survival. A substantial reduction of IL-38 was detected in the CRC tissue compared to adjacent non-cancer colonic tissue. IL-38 correlated with the extent of tumour differentiation (P < 0.0001); CRC location in the left side of the colon (P < 0.05), and smaller tumour size (≤ 5 cm; P < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated both high specificity and high sensitivity of IL-38 for the diagnosis of CRC [area under the curve (AUC) = 0.89)]. By sub-group analysis, AUC of IL-38 for the diagnosis of CRC was higher in poorly differentiated, right-sided CRC or tumour size > 5 cm (all AUC > 0.9). Significantly, longer survival was observed for the IL-38high versus the IL-38low groups in CRC patients (P = 0.04). Survival was also longer for IL-38high patients with lymph node metastasis (P = 0.01) and TNM stage III-IV (P = 0.02). Multivariate analysis demonstrated that IL-38 (P = 0.05) and tumour invasion depth (P = 0.04) were independent factors for survival. High IL38 in CRC is an independent prognostic factor for the longer survival of CRC patients. IL-38 signalling may constitute a therapeutic target in CRC.

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Abbreviations

AUC:

Area under the curve

AUROC:

AUC of the ROC curve

CRC:

Colorectal cancer

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DCs:

Dendritic cells

IL:

Interleukin

MAPK:

Mitogen-activated protein kinase

NFkB:

Nuclear factor kappa B

PD-1:

Programmed cell death protein 1

ROC:

Receiver operating characteristic

TNM:

Tumour, node and metastasis

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Acknowledgements

The authors acknowledge support from the staff of the Department of Pathology, Tongren Hospital, Shanghai Jiao University School of Medicine, and staff of the Discipline of Pathology, Sydney Medical School, The University of Sydney.

Funding

Shanghai Jiaotong University Medical Professional Cross Fund (Kun Tao) and the Joint Research Initiative Grant from Shanghai Jiaotong University, China (Kun Tao and Shisan Bao). The Natural Science Foundation of Shanghai, China 16ZR1432600 (Kun Tao), School of Medical Sciences, The University of Sydney Small Equipment Grant (Shisan Bao) and SJTU Research Project grant, The University of Sydney 2019 (Shisan Bao) are acknowledged.

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Authors and Affiliations

  1. Department of Pathology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Level 6, Building 6, Shanghai, 200050, China

    Feier Chen, Feng Zhang, Zhenyu Tan, Brett D. Hambly, Shisan Bao & Kun Tao

  2. Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkins Centre, The University of Sydney, Rm 4211 West, D17, Sydney, NSW, 2006, Australia

    Feier Chen, Brett D. Hambly & Shisan Bao

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  1. Feier Chen
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  2. Feng Zhang
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Contributions

FC: performed the experiment, analysed the data, and wrote the manuscript. FZ and ZT: performed histopathology. BH, SB and KT: designed the experiment and critically reviewed the manuscript. SB, and KT: provided financial support for the experiment.

Corresponding authors

Correspondence to Shisan Bao or Kun Tao.

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Conflict of interest

The authors declare there is no conflict of interest.

Ethical approval and ethical standards

Our current experiment has been approved by the Human Ethics Committee of Tongren Hospital, Shanghai Jiaotong University School of Medicine for the use of the tissues and the associated deidentified clinical data (ZH2018ZDA33). The guidelines of the Declaration of Helsinki on Medical Research involving human subjects has been strictly adhered to.

Informed consent

The oral consent for surgery included consent for the tissues to be used for diagnostic and research purposes in a deidentified manner. A written explanation of the surgical procedures and the potential research use of the tissues was provided to all patients prior to surgery. All of the patients were adults who were older than 16 years.

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Chen, F., Zhang, F., Tan, Z. et al. Interleukin-38 in colorectal cancer: a potential role in precision medicine. Cancer Immunol Immunother 69, 69–79 (2020). https://doi.org/10.1007/s00262-019-02440-7

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