Identification of SPP1 + macrophages as an immune suppressor in hepatocellular carcinoma using single-cell and bulk transcriptomics

Han Jin; Woonghee Kim; Meng Yuan; Xiangyu Li; Hong Yang; Mengzhen Li; Mengnan Shi; Hasan Turkez; Mathias Uhlen; Cheng Zhang; Adil Mardinoglu

doi:10.3389/fimmu.2024.1446453

Identification of SPP1 ⁺ macrophages as an immune suppressor in hepatocellular carcinoma using single-cell and bulk transcriptomics

Han Jin^*, Woonghee Kim, Meng Yuan, Xiangyu Li, Hong Yang, Mengzhen Li, Mengnan Shi, Hasan Turkez, Mathias Uhlen, Cheng Zhang, Adil Mardinoglu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Introduction: Macrophages and T cells play crucial roles in liver physiology, but their functional diversity in hepatocellular carcinoma (HCC) remains largely unknown. Methods: Two bulk RNA-sequencing (RNA-seq) cohorts for HCC were analyzed using gene co-expression network analysis. Key gene modules and networks were mapped to single-cell RNA-sequencing (scRNA-seq) data of HCC. Cell type fraction of bulk RNA-seq data was estimated by deconvolution approach using single-cell RNA-sequencing data as a reference. Survival analysis was carried out to estimate the prognosis of different immune cell types in bulk RNA-seq cohorts. Cell-cell interaction analysis was performed to identify potential links between immune cell types in HCC. Results: In this study, we analyzed RNA-seq data from two large-scale HCC cohorts, revealing a major and consensus gene co-expression cluster with significant implications for immunosuppression. Notably, these genes exhibited higher enrichment in liver macrophages than T cells, as confirmed by scRNA-seq data from HCC patients. Integrative analysis of bulk and single-cell RNA-seq data pinpointed SPP1⁺ macrophages as an unfavorable cell type, while VCAN⁺ macrophages, C1QA⁺ macrophages, and CD8⁺ T cells were associated with a more favorable prognosis for HCC patients. Subsequent scRNA-seq investigations and in vitro experiments elucidated that SPP1, predominantly secreted by SPP1⁺ macrophages, inhibits CD8⁺ T cell proliferation. Finally, targeting SPP1 in tumor-associated macrophages through inhibition led to a shift towards a favorable phenotype. Discussion: This study underpins the potential of SPP1 as a translational target in immunotherapy for HCC.

Original language	English
Article number	1446453
Journal	Frontiers in Immunology
Volume	15
Early online date	3 Dec 2024
DOIs	https://doi.org/10.3389/fimmu.2024.1446453
Publication status	Published - 3 Dec 2024

Keywords

co-expression network
hepatocellular carcinoma
macrophage heterogeneity
single-cell sequencing
tumor-associated macrophage

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@article{63e93e2a669643808567102e478bd35d,

title = "Identification of SPP1 + macrophages as an immune suppressor in hepatocellular carcinoma using single-cell and bulk transcriptomics",

abstract = "Introduction: Macrophages and T cells play crucial roles in liver physiology, but their functional diversity in hepatocellular carcinoma (HCC) remains largely unknown. Methods: Two bulk RNA-sequencing (RNA-seq) cohorts for HCC were analyzed using gene co-expression network analysis. Key gene modules and networks were mapped to single-cell RNA-sequencing (scRNA-seq) data of HCC. Cell type fraction of bulk RNA-seq data was estimated by deconvolution approach using single-cell RNA-sequencing data as a reference. Survival analysis was carried out to estimate the prognosis of different immune cell types in bulk RNA-seq cohorts. Cell-cell interaction analysis was performed to identify potential links between immune cell types in HCC. Results: In this study, we analyzed RNA-seq data from two large-scale HCC cohorts, revealing a major and consensus gene co-expression cluster with significant implications for immunosuppression. Notably, these genes exhibited higher enrichment in liver macrophages than T cells, as confirmed by scRNA-seq data from HCC patients. Integrative analysis of bulk and single-cell RNA-seq data pinpointed SPP1+ macrophages as an unfavorable cell type, while VCAN+ macrophages, C1QA+ macrophages, and CD8+ T cells were associated with a more favorable prognosis for HCC patients. Subsequent scRNA-seq investigations and in vitro experiments elucidated that SPP1, predominantly secreted by SPP1+ macrophages, inhibits CD8+ T cell proliferation. Finally, targeting SPP1 in tumor-associated macrophages through inhibition led to a shift towards a favorable phenotype. Discussion: This study underpins the potential of SPP1 as a translational target in immunotherapy for HCC.",

keywords = "co-expression network, hepatocellular carcinoma, macrophage heterogeneity, single-cell sequencing, tumor-associated macrophage",

author = "Han Jin and Woonghee Kim and Meng Yuan and Xiangyu Li and Hong Yang and Mengzhen Li and Mengnan Shi and Hasan Turkez and Mathias Uhlen and Cheng Zhang and Adil Mardinoglu",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 Jin, Kim, Yuan, Li, Yang, Li, Shi, Turkez, Uhlen, Zhang and Mardinoglu.",

year = "2024",

month = dec,

day = "3",

doi = "10.3389/fimmu.2024.1446453",

language = "English",

volume = "15",

journal = "Frontiers in Immunology",

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TY - JOUR

T1 - Identification of SPP1 + macrophages as an immune suppressor in hepatocellular carcinoma using single-cell and bulk transcriptomics

AU - Jin, Han

AU - Kim, Woonghee

AU - Yuan, Meng

AU - Li, Xiangyu

AU - Yang, Hong

AU - Li, Mengzhen

AU - Shi, Mengnan

AU - Turkez, Hasan

AU - Uhlen, Mathias

AU - Zhang, Cheng

AU - Mardinoglu, Adil

PY - 2024/12/3

Y1 - 2024/12/3

N2 - Introduction: Macrophages and T cells play crucial roles in liver physiology, but their functional diversity in hepatocellular carcinoma (HCC) remains largely unknown. Methods: Two bulk RNA-sequencing (RNA-seq) cohorts for HCC were analyzed using gene co-expression network analysis. Key gene modules and networks were mapped to single-cell RNA-sequencing (scRNA-seq) data of HCC. Cell type fraction of bulk RNA-seq data was estimated by deconvolution approach using single-cell RNA-sequencing data as a reference. Survival analysis was carried out to estimate the prognosis of different immune cell types in bulk RNA-seq cohorts. Cell-cell interaction analysis was performed to identify potential links between immune cell types in HCC. Results: In this study, we analyzed RNA-seq data from two large-scale HCC cohorts, revealing a major and consensus gene co-expression cluster with significant implications for immunosuppression. Notably, these genes exhibited higher enrichment in liver macrophages than T cells, as confirmed by scRNA-seq data from HCC patients. Integrative analysis of bulk and single-cell RNA-seq data pinpointed SPP1+ macrophages as an unfavorable cell type, while VCAN+ macrophages, C1QA+ macrophages, and CD8+ T cells were associated with a more favorable prognosis for HCC patients. Subsequent scRNA-seq investigations and in vitro experiments elucidated that SPP1, predominantly secreted by SPP1+ macrophages, inhibits CD8+ T cell proliferation. Finally, targeting SPP1 in tumor-associated macrophages through inhibition led to a shift towards a favorable phenotype. Discussion: This study underpins the potential of SPP1 as a translational target in immunotherapy for HCC.

AB - Introduction: Macrophages and T cells play crucial roles in liver physiology, but their functional diversity in hepatocellular carcinoma (HCC) remains largely unknown. Methods: Two bulk RNA-sequencing (RNA-seq) cohorts for HCC were analyzed using gene co-expression network analysis. Key gene modules and networks were mapped to single-cell RNA-sequencing (scRNA-seq) data of HCC. Cell type fraction of bulk RNA-seq data was estimated by deconvolution approach using single-cell RNA-sequencing data as a reference. Survival analysis was carried out to estimate the prognosis of different immune cell types in bulk RNA-seq cohorts. Cell-cell interaction analysis was performed to identify potential links between immune cell types in HCC. Results: In this study, we analyzed RNA-seq data from two large-scale HCC cohorts, revealing a major and consensus gene co-expression cluster with significant implications for immunosuppression. Notably, these genes exhibited higher enrichment in liver macrophages than T cells, as confirmed by scRNA-seq data from HCC patients. Integrative analysis of bulk and single-cell RNA-seq data pinpointed SPP1+ macrophages as an unfavorable cell type, while VCAN+ macrophages, C1QA+ macrophages, and CD8+ T cells were associated with a more favorable prognosis for HCC patients. Subsequent scRNA-seq investigations and in vitro experiments elucidated that SPP1, predominantly secreted by SPP1+ macrophages, inhibits CD8+ T cell proliferation. Finally, targeting SPP1 in tumor-associated macrophages through inhibition led to a shift towards a favorable phenotype. Discussion: This study underpins the potential of SPP1 as a translational target in immunotherapy for HCC.

KW - co-expression network

KW - hepatocellular carcinoma

KW - macrophage heterogeneity

KW - single-cell sequencing

KW - tumor-associated macrophage

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U2 - 10.3389/fimmu.2024.1446453

DO - 10.3389/fimmu.2024.1446453

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AN - SCOPUS:85212417452

SN - 1664-3224

VL - 15

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 1446453

ER -