Overexpressing S100A9 ameliorates NK cell dysfunction in estrogen receptor-positive breast cancer.


Journal

Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732

Informations de publication

Date de publication:
07 May 2024
Historique:
received: 08 02 2024
accepted: 01 04 2024
medline: 7 5 2024
pubmed: 7 5 2024
entrez: 7 5 2024
Statut: epublish

Résumé

Estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (ER+/HER2-BC) and triple-negative breast cancer (TNBC) are two distinct breast cancer molecular subtypes, especially in tumor immune microenvironment (TIME). The TIME of TNBC is considered to be more inflammatory than that of ER+/HER2-BC. Natural killer (NK) cells are innate lymphocytes that play an important role of tumor eradication in TME. However, studies focusing on the different cell states of NK cells in breast cancer subtypes are still inadequate. In this study, single-cell mRNA sequencing (scRNA-seq) and bulk mRNA sequencing data from ER+/HER2-BC and TNBC were analyzed. Key regulator of NK cell suppression in ER+/HER2-BC, S100A9, was quantified by qPCR and ELISA in MCF-7, T47D, MDA-MB-468 and MDA-MB-231 cell lines. The prognosis predictability of S100A9 and NK activation markers was evaluated by Kaplan-Meier analyses using TCGA-BRAC data. The phenotype changes of NK cells in ER+/HER2-BC after overexpressing S100A9 in cancer cells were evaluated by the production levels of IFN-gamma, perforin and granzyme B and cytotoxicity assay. By analyzing scRNA-seq data, we found that multiple genes involved in cellular stress response were upregulated in ER+/HER2-BC compared with TNBC. Moreover, TLR regulation pathway was significantly enriched using differentially expressed genes (DEGs) from comparing the transcriptome data of ER+/HER2-BC and TNBC cancer cells, and NK cell infiltration high/low groups. Among the DEGs, S100A9 was identified as a key regulator. Patients with higher expression levels of S100A9 and NK cell activation markers had better overall survival. Furthermore, we proved that overexpression of S100A9 in ER+/HER2-cells could improve cocultured NK cell function. In conclusion, the study we presented demonstrated that NK cells in ER+/HER2-BC were hypofunctional, and S100A9 was an important regulator of NK cell function in ER+BC. Our work contributes to elucidate the regulatory networks between cancer cells and NK cells and may provide theoretical basis for novel drug development.

Sections du résumé

BACKGROUND BACKGROUND
Estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (ER+/HER2-BC) and triple-negative breast cancer (TNBC) are two distinct breast cancer molecular subtypes, especially in tumor immune microenvironment (TIME). The TIME of TNBC is considered to be more inflammatory than that of ER+/HER2-BC. Natural killer (NK) cells are innate lymphocytes that play an important role of tumor eradication in TME. However, studies focusing on the different cell states of NK cells in breast cancer subtypes are still inadequate.
METHODS METHODS
In this study, single-cell mRNA sequencing (scRNA-seq) and bulk mRNA sequencing data from ER+/HER2-BC and TNBC were analyzed. Key regulator of NK cell suppression in ER+/HER2-BC, S100A9, was quantified by qPCR and ELISA in MCF-7, T47D, MDA-MB-468 and MDA-MB-231 cell lines. The prognosis predictability of S100A9 and NK activation markers was evaluated by Kaplan-Meier analyses using TCGA-BRAC data. The phenotype changes of NK cells in ER+/HER2-BC after overexpressing S100A9 in cancer cells were evaluated by the production levels of IFN-gamma, perforin and granzyme B and cytotoxicity assay.
RESULTS RESULTS
By analyzing scRNA-seq data, we found that multiple genes involved in cellular stress response were upregulated in ER+/HER2-BC compared with TNBC. Moreover, TLR regulation pathway was significantly enriched using differentially expressed genes (DEGs) from comparing the transcriptome data of ER+/HER2-BC and TNBC cancer cells, and NK cell infiltration high/low groups. Among the DEGs, S100A9 was identified as a key regulator. Patients with higher expression levels of S100A9 and NK cell activation markers had better overall survival. Furthermore, we proved that overexpression of S100A9 in ER+/HER2-cells could improve cocultured NK cell function.
CONCLUSION CONCLUSIONS
In conclusion, the study we presented demonstrated that NK cells in ER+/HER2-BC were hypofunctional, and S100A9 was an important regulator of NK cell function in ER+BC. Our work contributes to elucidate the regulatory networks between cancer cells and NK cells and may provide theoretical basis for novel drug development.

Identifiants

pubmed: 38713229
doi: 10.1007/s00262-024-03699-1
pii: 10.1007/s00262-024-03699-1
doi:

Substances chimiques

Calgranulin B 0
Receptors, Estrogen 0
S100A9 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

117

Subventions

Organisme : National Natural Science Foundation of China
ID : 82002791

Informations de copyright

© 2024. The Author(s).

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Auteurs

Yansong Liu (Y)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Mingcui Li (M)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Zhengbo Fang (Z)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Shan Gao (S)

Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Weilun Cheng (W)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Yunqiang Duan (Y)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Xuelian Wang (X)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Jianyuan Feng (J)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Tianshui Yu (T)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Jiarui Zhang (J)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Ting Wang (T)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Anbang Hu (A)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Hanyu Zhang (H)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Zhiyuan Rong (Z)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Suborna S Shakila (SS)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Yuhang Shang (Y)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Fanjing Kong (F)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Jiangwei Liu (J)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China.

Yanling Li (Y)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China. liyanling1016@163.com.

Fei Ma (F)

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Harbin, 150001, China. wafsfd@sina.com.

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Humans Male Smoking Cessation Cardiovascular Diseases Female
Humans United States Aged Cross-Sectional Studies Medicare Part C
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Humans Yoga Low Back Pain Female Male

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