Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance.

Humans Mice Animals Female Risk Factors Biomarkers, Tumor Immunologic Surveillance Neoplasms / diagnosis Lung Neoplasms / immunology Carcinoma, Non-Small-Cell Lung / immunology Male Breast Neoplasms / immunology Cell Line, Tumor

Immunosurveillance Immunotherapy Neuroendocrine factors Non-small cell lung cancer Precocious detection

Journal

Molecular cancer

ISSN: 1476-4598

Titre abrégé: Mol Cancer

Pays: England

ID NLM: 101147698

Informations de publication

Date de publication:
06 Sep 2024

Historique:

received: 27 05 2024

accepted: 21 08 2024

medline: 7 9 2024

pubmed: 7 9 2024

entrez: 6 9 2024

Statut: epublish

Résumé

The plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or 'endozepine') increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer. We measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing. Circulating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers. These findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.

RESULTS RESULTS

Circulating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.

CONCLUSION CONCLUSIONS

These findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

Identifiants

DOI: 10.1186/s12943-024-02098-5 PMID: 39242519

pubmed: 39242519

doi: 10.1186/s12943-024-02098-5

pii: 10.1186/s12943-024-02098-5

doi:

Substances chimiques

Biomarkers, Tumor 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

187

Subventions

Organisme : Xunta de Galicia

ID : IN606B-2021/015

Organisme : Ministerio de Ciencia, Innovación y Universidades

ID : FPU17/04473

Organisme : Agencia Estatal de Investigación

ID : 10.13039/501100011033

Organisme : Ministerio de Ciencia e Innovación

ID : PID2021-122695OB-I00

Informations de copyright

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