Dataset Information

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

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-1^highDPT 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.

SUBMITTER: Zheng B

PROVIDER: S-EPMC7341083 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Zheng Bo B Wang Dongfang D Qiu Xinyao X Luo Guijuan G Wu Tong T Yang Shuai S Li Zhixuan Z Zhu Yanjing Y Wang Shan S Wu Rui R Sui Chengjun C Gu Ziqi Z Shen Siyun S Jeong Seogsong S Wu Xuan X Gu Jin J Wang Hongyang H Chen Lei L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200518 13

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 en ...[more]

PMID: 32670760

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Project description:BackgroundPersonalized neoantigen vaccine could induce a robust antitumor immune response in multiple cancers, whose efficacy could be further enhanced by combining with programmed cell death 1 blockade (α-PD-1). However, the corresponding immune response and synergistic mechanisms remain largely unclear. Here, we aimed to develop clinically available combinational therapeutic strategy and further explore its potential antitumor mechanisms in hepatocellular carcinoma (HCC).MethodsNeoantigen peptide vaccine (NeoVAC) for murine HCC cell line Hepa1-6 was developed and optimized by neoantigen screening and adjuvant optimization. Then the synergistic efficacy and related molecular mechanisms of NeoVAC combined with α-PD-1 in HCC were evaluated by orthotopic HCC mouse model, single-cell RNA sequencing, tetramer flow cytometry, immunofluorescence, etc. The tumor-killing capacity of CD8+ tissue-resident memory T cells (CD8+ TRMs) was assessed by orthotopic HCC mouse model, and autologous patient-derived cells.ResultsNeoVAC, which consisted of seven high immunogenic neoantigen peptides and clinical-grade Poly(I:C), could generate a strong antitumor immune response in HCC mouse models. Significantly, its efficacy could be further improved by combining with α-PD-1, with 80% of durable tumor regression and long-term immune memory in orthotopic HCC models. Moreover, in-depth analysis of the tumor immune microenvironment showed that the percentage of CD8+ TRMs was remarkedly increased in NeoVAC plus α-PD-1 treatment group, and positively associated with the antitumor efficacy. In vitro and in vivo T-cell cytotoxicity assay further confirmed the strong tumor-killing capacity of CD8+ TRMs sorting from orthotopic mouse HCC or patient's HCC tissue.ConclusionsThis study showed that NeoVAC plus α-PD-1 could induce a strong antitumor response and long-term tumor-specific immune memory in HCC by increasing CD8+ TRMs infiltration, which might serve as a potential immune-therapeutic target for HCC.

Dataset Information

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

Publications

Trajectory and Functional Analysis of PD-1<sup>high</sup> CD4<sup>+</sup>CD8<sup>+</sup> T Cells in Hepatocellular Carcinoma by Single-Cell Cytometry and Transcriptome Sequencing.

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