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Molecular Diagnostics

TIM3+ cells in gastric cancer: clinical correlates and association with immune context

British Journal of Cancer volume 126, pages 100–108 (2022)Cite this article

Subjects

Abstract

Background

T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a crucial immune checkpoint and is considered as an emerging target for cancer treatment. However, the clinical significance and immune-related role of TIM3+ cells in gastric cancer remain unknown. This study aimed to investigate the clinical significance of tumour-infiltrating TIM3+ cells and their association with immune contexture in gastric cancer.

Methods

This study enrolled three cohorts, including 436 tumour tissue microarray specimens and 58 fresh tumour tissues of gastric cancer patients from Zhongshan Hospital, and 330 transcriptional data from The Cancer Genome Atlas. TIM3+ cells and their association with CD8+ T cells were evaluated by immunohistochemistry and flow cytometry analyses. Kaplan–Meier curves, Cox model and interaction test were performed to assess clinical outcomes.

Results

Tumour-infiltrating TIM3+ cells’ high subgroups experienced poorer overall survival and disease-free survival and predicted inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. TIM3 indicated CD8+ T cell dysfunction, which impeded chemotherapeutic responsiveness. Besides, HAVCR2 messenger RNA expression was associated with specific molecular characteristics.

Conclusions

The abundance of tumour-infiltrating TIM3+ cells could identify an immunoevasive subtype gastric cancer with CD8+ T cell dysfunction, suggesting that TIM3 might serve as a promising target for immunotherapy in gastric cancer.

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Fig. 1: TIM3+ cells are densely infiltrated in gastric cancer tissues and associated with disease progression.
Fig. 2: Tumour-infiltrating TIM3+ cells predict poor prognosis in gastric cancer patients.
Fig. 3: Relationship between tumour-infiltrating TIM3+ cells and responsiveness to ACT.
Fig. 4: Tumour-infiltrating TIM3+ cells are associated with dysfunctional CD8+ T cells.
Fig. 5: TIM3-associated CD8+ T cell dysfunction indicates inferior chemotherapeutic responsiveness in gastric cancer.
Fig. 6: Characterisation of molecular subtypes based on HAVCR2 mRNA expression.

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Data availability

All data generated that are relevant to the results presented in this article are included in this article. Other data that were not relevant for the results presented here are available from the corresponding author Dr. Xu upon reasonable request.

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Acknowledgements

We thank Dr. Lingli Chen (Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China) and Dr. Yunyi Kong (Department of Pathology, Shanghai Cancer Centre, Fudan University, Shanghai, China) for their excellent pathological technology help.

Funding

This study was funded by grants from the National Natural Science Foundation of China (31770851, 81871930, 81902402, 81902901, 81972219, 82003019 and 82103313) and Shanghai Sailing Programme (18YF1404600, 19YF1407500 and 21YF1407600). All the sponsors have no roles in the study design, in the collection, analysis and interpretation of data.

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Author notes

  1. These authors contributed equally: Ke Chen, Yun Gu, Yifan Cao.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Ke Chen, Yun Gu, Hanji Fang, Kunpeng Lv, Xin Liu, Xudong He & Jiejie Xu

  2. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Yifan Cao, Chao Lin, Hao Liu, Heng Zhang, Hongyong He, He Li & Ruochen Li

  3. Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Jieti Wang

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Contributions

K.C., Y.G. and Y.C.: acquisition of data, analysis and interpretation of data, statistical analysis and drafting of the manuscript; H.F., K.L., X.L., X.H., J.W., C.L., H.L., H.Z. and H.H.: technical and material support; J.X., H.L. and R.L.: study concept and design, analysis and interpretation of data, drafting of the manuscript and obtained funding and study supervision. All authors read and approved the final manuscript.

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Correspondence to Jiejie Xu, He Li or Ruochen Li.

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The authors declare no competing interests.

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The study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University. Written informed consent was obtained from each patient included and this study was performed in accordance with the Declaration of Helsinki.

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Chen, K., Gu, Y., Cao, Y. et al. TIM3+ cells in gastric cancer: clinical correlates and association with immune context. Br J Cancer 126, 100–108 (2022). https://doi.org/10.1038/s41416-021-01607-3

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