Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, China.
Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Jan 1;1869(1):166591. doi: 10.1016/j.bbadis.2022.166591. Epub 2022 Oct 31.
Extensive infiltration of tumor-associated macrophages was correlated poor prognosis in anaplastic thyroid cancer (ATC). However, the heterogeneity and characteristics of the ATC-associated macrophages (ATAMs) in ATC remain far from clear. We combined single-cell RNA-sequencing analysis and gene expression microarray datasets to assess the molecular signature of ATAMs. Compared with normal thyroid-associated macrophages (NTAMs), 778 differentially expressed genes (DEGs) significantly changed in ATAMs compared with NTAMs. These DEGs were correlated with oxidative phosphorylation (M2 phenotype) and phagocytosis (M1 phenotype). Moreover, ATAMs highly expressed pro-tumor genes associated with angiogenesis, fibrosis, metalloprotease activity, and metastasis. Notably, we identified one ATC-specific subset, IL2RA VSIG4 ATAMs, co-expressed M1 and M2 markers. The infiltration of IL2RA VSIG4 ATAMs showed strong correlation with BRAF and RAS signaling, and its high infiltration was associated with favorable prognosis in thyroid-cancer patients. IL2RA VSIG4 ATAMs were associated with increased tumor-infiltrating lymphocytes (B cells, CD8 T cells, Tregs). IL2RA VSIG4 ATAMs interacted with CD8 T cells and Tregs through immune checkpoints (such as LGALS9_HAVCR2), cytokines (such as CXCL10_CXCR3), and receptors (such as CSF1R_CSF1), thereby forming an immunosuppressive microenvironment. Multiplex immunohistochemistry staining and coculture experiment confirmed that ATC cancer cells were able to induce the polarization of IL2RA VSIG4 ATAMs. Besides, we identified several novel ATC-specific immune checkpoint genes including the immunosuppressive molecule VSIG4, LAIR1, and LILRB2. Expression of VSIG4 was also significantly correlated with tumor-infiltrating lymphocytes (B cells, CD8 T cells, Tregs). In conclusion, our study revealed an ATC-specific ATAM subset with bifunctional phenotype, which provided a comprehensive insight to delineate the molecular characteristics of ATC-associated macrophages.
肿瘤相关巨噬细胞（TAMs）的广泛浸润与间变性甲状腺癌（ATC）的不良预后相关。然而，ATC 中 TAMs 的异质性和特征仍远未清楚。我们结合单细胞 RNA 测序分析和基因表达微阵列数据集来评估 ATAMs 的分子特征。与正常甲状腺相关巨噬细胞（NTAMs）相比，ATAMs 中 778 个差异表达基因（DEGs）与 NTAMs 相比有显著变化。这些 DEGs 与氧化磷酸化（M2 表型）和吞噬作用（M1 表型）相关。此外，ATAMs 高度表达与血管生成、纤维化、金属蛋白酶活性和转移相关的促肿瘤基因。值得注意的是，我们鉴定出一个 ATC 特异性亚群，即 IL2RA VSIG4 ATAMs，其共表达 M1 和 M2 标志物。IL2RA VSIG4 ATAMs 的浸润与 BRAF 和 RAS 信号强烈相关，其高浸润与甲状腺癌患者的良好预后相关。IL2RA VSIG4 ATAMs 与肿瘤浸润淋巴细胞（B 细胞、CD8 T 细胞、Tregs）的增加有关。IL2RA VSIG4 ATAMs 通过免疫检查点（如 LGALS9_HAVCR2）、细胞因子（如 CXCL10_CXCR3）和受体（如 CSF1R_CSF1）与 CD8 T 细胞和 Tregs 相互作用，从而形成免疫抑制微环境。多重免疫组化染色和共培养实验证实，ATC 癌细胞能够诱导 IL2RA VSIG4 ATAMs 的极化。此外，我们还鉴定了几个新的 ATC 特异性免疫检查点基因，包括免疫抑制分子 VSIG4、LAIR1 和 LILRB2。VSIG4 的表达也与肿瘤浸润淋巴细胞（B 细胞、CD8 T 细胞、Tregs）显著相关。总之，我们的研究揭示了一个具有双功能表型的 ATC 特异性 ATAM 亚群，为描绘 ATC 相关巨噬细胞的分子特征提供了全面的见解。
