Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma.
Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma.
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DOI：
10.1186/s12967-022-03620-3
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发表时间：
2022-09-23
影响因子：
7.4
通讯作者：
Zhang, Peng
中科院分区：
文献类型：
--
作者：
Li, Dianke;Yu, Huansha;Hu, Junjie;Li, Shaoling;Yan, Yilv;Li, Shuangyi;Sun, Liangdong;Jiang, Gening;Hou, Likun;Zhang, Lele;Zhang, Peng
组织学组成的多样性反映了肺腺癌（LUAD）宏观上的肿瘤间和肿瘤内异质性。在单细胞水平上深入了解 LUAD 不同组织学亚型的肿瘤学特征和肿瘤微环境 (TME)，有助于识别潜在的治疗漏洞和组合方法，以提高 LUAD 患者的生存率。通过对 scRNA-seq 数据定义的细胞群落进行比较分析，我们表征了不同组织学亚型的 LUAD 样本的 TME，并在多个批量转录组、蛋白质组数据集和独立的免疫组织化学验证队列中进一步证实了相关结果。我们发现，与其他组织学亚型相比，固体 LUAD 的 TME 中缺氧和酸性情况最差。此外，肿瘤代谢偏好因组织学亚型而异，可能相应地影响免疫细胞的代谢和功能。值得注意的是，来自固体LUAD的肿瘤细胞上调能量和物质代谢活动，特别是叶酸介导的一碳代谢和关键基因MTHFD2，这可以作为潜在的治疗靶点。此外，泛素化修饰也可能参与组织学模式的进展。从免疫学角度来看，固体 LUAD 的特点是主要是耗尽的 T 细胞和免疫抑制性骨髓细胞，其中缺氧、酸化和营养缺乏的 TME 具有不可忽视的影响。不同程度的基质重塑和纤维化证明了基质细胞功能的差异，也可能导致固体 LUAD 的特异性免疫表型。总体而言，我们的研究提出了几个潜在的切入点来改善固体LUAD的免疫抑制TME，从而协同增强其免疫治疗功效，并可能为不同组织学亚型构成的LUAD患者提供精确的治疗策略。在线版本包含可在 10.1186/s12967-022-03620-3 获取的补充材料。
The diversity of histologic composition reflects the inter- and intra-tumor heterogeneity of lung adenocarcinomas (LUADs) macroscopically. Insights into the oncological characteristics and tumor microenvironment (TME) of different histologic subtypes of LUAD at the single-cell level can help identify potential therapeutic vulnerabilities and combinational approaches to improve the survival of LUAD patients. Through comparative profiling of cell communities defined by scRNA-seq data, we characterized the TME of LUAD samples of distinct histologic subtypes, with relevant results further confirmed in multiple bulk transcriptomic, proteomic datasets and an independent immunohistochemical validation cohort. We find that the hypoxic and acidic situation is the worst in the TME of solid LUADs compared to other histologic subtypes. Besides, the tumor metabolic preferences vary across histologic subtypes and may correspondingly impinge on the metabolism and function of immune cells. Remarkably, tumor cells from solid LUADs upregulate energy and substance metabolic activities, particularly the folate-mediated one-carbon metabolism and the key gene MTHFD2, which could serve as a potential therapeutic target. Additionally, ubiquitination modifications may also be involved in the progression of histologic patterns. Immunologically, solid LUADs are characterized by a predominance of exhausted T cells and immunosuppressive myeloid cells, where the hypoxic, acidified and nutrient-deprived TME has a non-negligible impact. Discrepancies in stromal cell function, evidenced by varying degrees of stromal remodeling and fibrosis, may also contribute to the specific immune phenotype of solid LUADs. Overall, our research proposes several potential entry points to improve the immunosuppressive TME of solid LUADs, thereby synergistically potentiating their immunotherapeutic efficacy, and may provide precise therapeutic strategies for LUAD patients of distinct histologic subtype constitution. The online version contains supplementary material available at 10.1186/s12967-022-03620-3.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.6
作者：
Du X;Song H;Shen N;Hua R;Yang G
通讯作者：
Yang G
DOI：
10.1038/s41571-021-00546-5
发表时间：
2021-12
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Chen Y;McAndrews KM;Kalluri R
通讯作者：
Kalluri R
DOI：
10.1016/j.jtho.2020.08.005
发表时间：
2020-12
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Caso R;Sanchez-Vega F;Tan KS;Mastrogiacomo B;Zhou J;Jones GD;Nguyen B;Schultz N;Connolly JG;Brandt WS;Bott MJ;Rocco G;Molena D;Isbell JM;Liu Y;Mayo MW;Adusumilli PS;Travis WD;Jones DR
通讯作者：
Jones DR
影响因子：
64.5
作者：
Gillette, Michael A.;Satpathy, Shankha;Carr, Steven A.
通讯作者：
Carr, Steven A.