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Toll-like receptors 1, 2, 4, 5, and 6 in gastric cancer

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Abstract

Toll-like receptors (TLRs) are expressed on both immune cells and tumor cells, triggering both anti-tumor and pro-tumor responses. Therefore, TLRs have potential as prognostic biomarkers and immunotherapeutic targets. The aim of this study was to investigate TLR1, TLR2, TLR4, TLR5, and TLR6 expression and association with clinicopathological variables and survival in gastric cancer. Immunohistochemical study on cancer specimens from 564 resected gastric cancer patients was performed using tissue microarrays. The association between patient survival and TLR expression was calculated with Cox regression adjusted for confounding factors. Patients with high cytoplasmic TLR2 expression had significantly poorer 5-year survival than the low cytoplasmic TLR2 expression group in multivariate analysis (adjusted HR 1.38, 95% CI 1.11–1.71), and this estimate was similar in intestinal type (adjusted HR 1.33, 95% CI 0.98–1.80) and diffuse type (adjusted HR 1.48, 95% CI 1.06–2.05) histology subgroups. Patients with high cytoplasmic TLR6 expression group had significantly better 5-year survival compared with low cytoplasmic TLR6 expression group in multivariate analysis (adjusted HR 0.74, 95% CI 0.60–0.91). In the subgroup analysis of diffuse type of histology, the 5-year survival was better in high cytoplasmic TLR6 expression group in multivariable analysis (HR 0.62, 95% CI 0.46–0.83). In the intestinal type of histology subgroup, no significant differences between the groups were present. TLR1, TLR4, and TLR5 expression were not associated with 5-year survival. In conclusion, cytoplasmic TLR2 and TLR6 expression seem to have independent prognostic impact in gastric cancer, while TLR1, TLR4, and TLR5 do not.

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Data are available upon reasonable request from the corresponding author.

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Acknowledgements

We thank Erja Tomperi and Riitta Vuento for important technical assistance. The study benefited from samples/data from Northern Finland Biobank Borealis, Oulu, Finland.

Funding

This study was supported by grants from The Finnish Medical Foundation (M.E.), The Maud Kuistila Memorial Foundation (M.E.), Orion Research Foundation (J.H.K.), Thelma Mäkikyrö Foundation (J.H.K.), and Mary and Georg C. Ehrnroot Foundation (J.H.K.), Päivikki and Sakari Sohlberg Foundation (J.H.K.), The Finnish Cancer Foundation (J.H.K.), and Sigrid Juselius Foundation (J.H.K.).

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Authors and Affiliations

  1. Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Aapistie 5, P.O. Box 5000, 90014, Oulu, Finland

    Maarit Eskuri, Niko Kemi, Olli Helminen, Heikki Huhta & Joonas H Kauppila

  2. Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Joonas H Kauppila

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  1. Maarit Eskuri
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Contributions

All the authors conceived and designed the study. N.K., O.H., H.H., and J.H.K. acquired the data. M.E. and N.K. performed the experiments. M.E. analyzed the data, drafted the manuscript, and prepared the original figures and tables. All the authors critically reviewed, edited, and approved the manuscript. J.H.K provided funding, supervised the study, and is the guarantor of the study.

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Correspondence to Maarit Eskuri.

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Ethics approval

The use of patient samples and the data inquiry were approved by the Oulu University Hospital Ethics Committee (15.2.2016 §51). The need to obtain a written or oral consent from the patients was waived by the Finnish National Authority for Medicolegal Affairs (VALVIRA). This study was performed in accordance with the Declaration of Helsinki.

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Supplementary file1 (DOCX 45 KB)

Supplementary Figure 1.

Representative images of TLR1, TLR4 and TLR5 expression immunostaining in gastric adenocarcinoma. Low cytoplasmic TLR1 expression (A), high cytoplasmic TLR1 expression (B), low cytoplasmic TLR4 expression (C), high cytoplasmic TLR4 expression (D), low membranous TLR4 expression (E), high membranous TLR4 expression (F), low cytoplasmic TLR5 expression (G), high cytoplasmic TLR5 expression (H), low nuclear TLR5 expression (I), and high nuclear TLR5 expression (J). (PNG 2.57 Mb).

High resolution image (TIF 54.9 mb).

Supplementary Figure 2.

The Kaplan-Meier figures presenting 5-year survival stratified by Toll-like receptor expressions in gastric adenocarcinoma, with p values for significance based on the log-rank test. Cytoplasmic TLR1 expression (A), cytoplasmic TLR4 expression (B), membranous TLR4 expression (C), cytoplasmic TLR5 expression (D), and nuclear TLR5 expression (E). (PNG 9.21 mb).

High resolution image (TIF 49.1 mb).

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Eskuri, M., Kemi, N., Helminen, O. et al. Toll-like receptors 1, 2, 4, 5, and 6 in gastric cancer. Virchows Arch (2023). https://doi.org/10.1007/s00428-023-03635-1

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