Papillary Thyroid Carcinoma Landscape and Its Immunological Link With Hashimoto Thyroiditis at Single-Cell Resolution.

Jun Pan,Yijun Wu,Qinsheng Zhu,Guoji Guo,Minjie Zhu,Yibin Shen,Yunjin Yao,Yaohui Zhang,Feng Zhu,Jiaqi Li,Xinhui Zhou,Chengxuan Yu,Fang Ye,Hedi Tian,Yingying Wang

doi:10.3389/fcell.2021.758339

Abstract

The tumor microenvironment heterogeneity of papillary thyroid cancer (PTC) is poorly characterized. The relationship between PTC and Hashimoto thyroiditis (HT) is also in doubt. Here, we used single-cell RNA sequencing to map the transcriptome landscape of PTC from eight PTC patients, of which three were concurrent with HT. Predicted copy number variation in epithelial cells and mesenchymal cells revealed the distinct molecular signatures of carcinoma cells. Carcinoma cells demonstrated intertumoral heterogeneity based on BRAF V600E mutation or lymph node metastasis, and some altered genes were identified to be correlated with disease-free survival in The Cancer Genome Atlas datasets. In addition, transcription factor regulons of follicular epithelial cells unveil the different transcription activation state in PTC patients with or without concurrent HT. The immune cells in tumors exhibited distinct transcriptional states, and the presence of tumor-infiltrating B lymphocytes was predominantly linked to concurrent HT origin. Trajectory analysis of B cells and plasma cells suggested their migration potential from HT adjacent tissues to tumor tissues. Furthermore, we revealed diverse ligand–receptor pairs between non-immune cells, infiltrating myeloid cells, and lymphocytes. Our results provided a single-cell landscape of human PTC. These data would deepen the understanding of PTC, as well as the immunological link between PTC and HT.

Highlights

Thyroid cancer is the most common endocrine malignancy worldwide, with significant increases in incidence around the world over the past three decades (Pellegriti et al, 2013)
Inferred copy number variations (CNV) in parenchymal cells identified predicted tumor cells in follicular epithelial cells and mesenchymal cells with strong epithelial–mesenchymal transition (EMT) properties, which may lead to tumor progression and metastasis
The BRAF V600E mutation confers an aggressive phenotype in Papillary thyroid cancer (PTC), and a previous study has used RNA-seq to identify differentially expressed genes (DEGs) between BRAF V600E mutation and BRAF wild-type tumors (Smallridge et al, 2014)

Summary

Introduction

Thyroid cancer is the most common endocrine malignancy worldwide, with significant increases in incidence around the world over the past three decades (Pellegriti et al, 2013). The global incidence rate in women is 10.2 per 100,000, and that in men is 3.1 per 100,000 This disease represents 5.1% of all estimated female cancer burden (Bray et al, 2018). Gene expression–based molecular subtyping of PTC could be potentially used as a prognostic tool with important clinical relevance. Some studies have reported a correlation between positive or negative clinical outcomes in thyroid cancer patients and tumorinfiltrating immune cells (Gooden et al, 2011; Gentles et al, 2015). Myeloid-derived suppressor cells are elevated in cancer patients, where they show a strong immunosuppressive potential, and are associated with a poor prognosis (Gabrilovich and Nagaraj, 2009). The frequency of tumor-associated macrophages (TAMs) changes in the distinct subtypes of thyroid cancer (Jung et al, 2015).

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