Journal Article

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma

Sun, Yuanjue, Shen, Zan, Lv, Xiaobin, Yin, Junyi, Fei, Jia, Hu, Haiyan, Qian, Binzhi, Chen, Peizhan, Yu, Wenxi, Huang, Wentao, Zhou, Yan, Ding, Xiaomin, Wang, Yonggang, Yuan, Ting, Yang, Dong, Su, Yang, Pan, Xinghua, Tang, Lina, Zhou, Chenliang, He, Aina, Meng, Wei, Yao, Yang, Zhang, Zhichang, Huang, Yujing, Zhang, Jianjun, Wang, Yaling, Yang, Qingcheng, Zhou, Zhenhua

2020

Overview

Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4 + macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3 + T cells with high proportion of TIGIT + cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma. Osteosarcomas are difficult to treat and have a limited response to immunotherapy. Here, the authors analyse osteosarcomas at the single-cell level, and identify both the transdifferentiation of malignant cells and an array of immune cells that could have implications for metastasis and immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/51 / 38 / 38/91 / 49 / 631/67/1344 / 631/67/2329 / 631/67/327 / 692/4028/67/1798 / Adolescent / Adult / Biomedical materials / Bone cancer / Bone tumors / Cancer-Associated Fibroblasts - pathology / CD3 antigen / Cell Aggregation - genetics / Child / Clone Cells / Clustering / Cytotoxicity / Dendritic Cells - pathology / DNA Copy Number Variations - genetics / Female / Gene expression / Gene sequencing / Genetic Heterogeneity / Heterogeneity / Humanities and Social Sciences / Humans / Immune system / Immunosuppression Therapy / Immunotherapy / Infiltration / Inflammation / Lesions / Lungs / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Macrophages / Macrophages - pathology / Male / Mesenchymal Stem Cells - pathology / Metastases / Metastasis / multidisciplinary / Myeloid Cells - pathology / Neoplasm Staging / Osteoblasts / Osteoclasts / Osteoclasts - metabolism / Osteoclasts - pathology / Osteosarcoma / Osteosarcoma - genetics / Osteosarcoma - immunology / Osteosarcoma - pathology / Ribonucleic acid / RNA / RNA, Neoplasm - genetics / RNA, Neoplasm - metabolism / Sarcoma / Science / Science (multidisciplinary) / Single-Cell Analysis / Stromal Cells - pathology / Toxicity / Transcriptome - genetics / Transcriptomics / Tumor Microenvironment - immunology / Tumors / Young Adult