Trajectory and Functional Analysis of PD‐1high CD4+CD8+ T Cells in Hepatocellular Carcinoma by Single‐Cell Cytometry and Transcriptome Sequencing

Advanced Science

Rui Wu¹  Xuan Wu²  Seogsong Jeong³  Shuai Yang⁴  Shan Wang⁴  Xinyao Qiu⁴  Dongfang Wang⁵  Jin Gu⁵  Ziqi Gu⁶  Zhixuan Li⁶  Lei Chen⁶  Siyun Shen⁶  Chengjun Sui⁶  Guijuan Luo⁶  Hongyang Wang⁶  Tong Wu⁶  Bo Zheng⁶  Yanjing Zhu⁶ 

[1] Department of Biliary Surgery I Eastern Hepatobiliary Surgery Hospital Second Military Medical University Changhai Road 225 Shanghai 200438 China;Department of Laboratory Medicine The Tenth People's Hospital of Shanghai Tongji University Shanghai 200072 China;Department of Liver Surgery Renji Hospital School of Medicine Shanghai JiaoTong University Shanghai 200127 China;Fudan University Shanghai Cancer Center Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 China;MOE Key Laboratory for Bioinformatics BNRIST Bioinformatics Division Department of Automation Tsinghua University Beijing 100084 China;National Center for Liver Cancer Shanghai 200438 China;

关键词: double positive T cells;    liver cancer;    mass cytometry;    single‐cell sequencing;    tumor microenvironment;   

DOI  :  10.1002/advs.202000224

来源: DOAJ

【 摘 要 】

Abstract The spatial heterogeneity of immune microenvironment in hepatocellular carcinoma (HCC) remains elusive. Here, a single‐cell study involving 17 432 600 immune cells of 39 matched HCC (T), nontumor (N), and leading‐edge (L) specimens by mass cytometry is conducted. The tumor‐associated CD4/CD8 double‐positive T (DPT) cells are found enriched in L regions with synergetic expression of PD‐1/HLA‐DR/ICOS/CD45RO and exhibit a higher level of IFN‐γ, TNF‐α, and PD‐1 upon stimulation. The enrichment of DPT and PD‐1+DPT in L regions indicates favorable prognosis. These tumor‐associated DPT cells with similar phenotype are also verified in other tumors and HCC animal models. Single‐cell RNA‐seq further characterizes the molecular features of DPT cells and uncovers 11 clusters with different cytotoxicity, exhaustion, and activation scores. TCR‐based trajectory analysis reveals that tumor‐associated DPT clusters share separated ancestries with local CD4+ or CD8+SPT cells rather than CD3+PBMC cells. TCR clones with frequency above 10 are mainly found coexisting in DPT and CD8+SPT cells. Specifically, PD‐1highDPT cluster (TDPT_10) shares the same ancestry with exhausted CD8+SPT cluster (TCD8T_2) and shows higher expression similarity and closer pathological location to PD‐1+CD8+ than PD‐1+CD4+T cells. Together, this study systematically characterizes the unique distribution of PD‐1+DPTs in HCC and puts forward new insights for the function and origin of tumor‐associated DPT cells.

【 授权许可】

Unknown