Taylor Aaron Michael, Sheng Jianting, Ng Patrick Kwok Shing, Harder Jeffrey M, Kumar Parveen, Ahn Ju Young, Cao Yuliang, Dzis Alissa M, Jillette Nathaniel L, Goodspeed Andrew, Bodlak Avery, Wu Qian, Isakoff Michael S, George Joshy, Grassmann Jessica D S, Luo Diane, Flynn William F, Courtois Elise T, Robson Paul, Hayashi Masanori, Paolillo Alini Trujillo, Petrilli Antonio Sergio, Caminada de Toledo Silvia Regina, Balarezo Fabiola Sara, Lindsay Adam D, Hoang Bang, Wong Stephen T C, Lau Ching C
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Systems Medicine and Bioengineering Department, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA.
Cancers (Basel). 2025 Jun 24;17(13):2117. doi: 10.3390/cancers17132117.
Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for the validation of discovered subtypes and to add spatial context. Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T cells, and LAMP3+ dendritic cells. Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche.
骨肉瘤是儿童最常见的恶性骨肿瘤，其特征是高度的基因组不稳定，导致拷贝数改变和基因组重排，而无明确疾病的复发性突变。在过去40年中，基于分子特征的临床试验未能找到新的有效疗法或改善治疗结果。为了更好地了解骨肉瘤的免疫微环境，我们对6个肿瘤活检样本进行了单细胞RNA测序，并结合了之前发表的6个样本队列。使用空间转录组学对额外的骨肉瘤样本进行分析，以验证发现的亚型并增加空间背景信息。分析揭示了免疫抑制细胞，包括髓源性抑制细胞（MDSC）、调节性T细胞和耗竭性T细胞，以及LAMP3+树突状细胞。通过细胞间通讯建模，我们确定了MDSC与其他细胞之间的强烈相互作用，导致NF-κB上调和免疫抑制微环境，以及涉及调节性T细胞和骨肉瘤细胞的相互作用，这些相互作用促进了肿瘤进展和促血管生成微环境。
