Abstract
Lymph node metastases are strongly associated with unfavorable prognosis in papillary thyroid carcinoma (PTC) patients. However, there are few sensitive or specific indicators that can diagnose or predict lymph node metastases in PTC. The objective of our study was to identify reliable indicators for the diagnosis and prediction of lymph node metastases of PTC. The PTC data set was obtained from The Cancer Genome Atlas (TCGA) cohort. Information on tumor-infiltrating immune cells in PTC was acquired using single-sample gene set enrichment analysis (ssGSEA). Then, the progression-free survival (PFS) rates of PTC patients were evaluated by Kaplan–Meier curves. A tissue microarray including 58 normal thyroid tissues and 57 PTC tissues was processed for CD19 immunohistochemistry staining. Finally, evaluation of phenotype permutations was performed using gene set enrichment analysis (GSEA). There was an appreciable association between immune infiltration and lymph node metastases in PTC. Among those immune cells, B cells and cytotoxic cells showed significant predictive accuracy for lymph node metastases in PTC. Tumor-infiltrating B cells and NK cells were associated with favorable prognosis, while tumor-associated NK CD56bright cells were correlated with poor prognosis in PTC patients. IHC analyses of PTC further confirmed a notably negative correlation between B cell infiltration and lymph node metastases in PTC. Additionally, mutations in BRAF, a dominant cause of tumor mutation burden (TMB), were positively correlated with reduced B cell infiltration and lymph node metastases in PTC. GSEA revealed that epithelial-mesenchymal transition, IL-6/JAK/STAT3 signaling, the inflammatory response, and TNF-α signaling via the NFκB pathway were remarkably suppressed pathways in patients with BRAF mutations. Tumor-associated lymphocytic infiltration, especially B cell infiltration, provides diagnostic and prognostic value for lymph node metastases in PTC.
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All data generated or analyzed during this study are included in the article and its supplementary files.
Abbreviations
- AUC:
-
Area under the ROC curve
- GSEA:
-
Gene set enrichment analysis
- HR:
-
Hazard ratio
- IHC:
-
Immunohistochemistry
- NK:
-
Natural killer
- ROC:
-
Receiver operating characteristic
- ssGSEA:
-
Single-sample gene set enrichment analysis
- TCGA:
-
The Cancer Genome Atlas
- PTC:
-
Papillary thyroid carcinoma
- TMB:
-
Tumor mutation burden
- 95% CI:
-
95% Confidence interval
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Acknowledgements
Special thanks to Shanghai Outdo Biotech Co., Ltd., for helping us create the tissue microarray. Thank you to Dr. Ya Xiao for guidance in data analysis.
Funding
This work was supported by grants from the National Natural Science Foundation of China (grant no. 81602730) and Medical Technology Innovation Fund of Chongqing General Hospital (Y2020ZDXM06).
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Designed the research: ZY, FZ, and WY; acquisition of data: ZY; analysis and interpretation of data: ZY and WY; collection of human PTC and normal thyroid tissue microarray: LY, YZ, YL, HC, and SY; draft of the manuscript: WY and ZY; critical revision of the manuscript: FZ and WY; funding acquisition: LY and ZY. All authors read, revised, and approved the final manuscript.
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Ethics approval for this study was granted by the Institute Research Medical Ethics Committee of the Shanghai Outdo Biotech Company. Written informed consent was obtained from all patients.
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Additional File 1
Supplementary Figure 1. Coexpression patterns among diverse immune cells. (PDF 48 kb)
Additional File 2
Supplementary Figure 2. Coexpression patterns between B cell infiltration and immunosuppressive markers. (PDF 8 kb)
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Yang, Z., Yin, L., Zeng, Y. et al. Diagnostic and prognostic value of tumor-infiltrating B cells in lymph node metastases of papillary thyroid carcinoma. Virchows Arch 479, 947–959 (2021). https://doi.org/10.1007/s00428-021-03137-y
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DOI: https://doi.org/10.1007/s00428-021-03137-y