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

• Published in: Molecular cancer Vol. 23; no. 1; pp. 187 - 19
• Main Authors: Montégut, Léa, Liu, Peng, Zhao, Liwei, Pérez-Lanzón, María, Chen, Hui, Mao, Misha, Zhang, Shuai, Derosa, Lisa, Naour, Julie Le, Lambertucci, Flavia, Mingoia, Silvia, Nogueira-Recalde, Uxía, Mena-Osuna, Rafael, Herranz-Montoya, Irene, Djouder, Nabil, Baulande, Sylvain, Pan, Hui, Joseph, Adrien, Messaoudene, Meriem, Routy, Bertrand, Fidelle, Marine, Ahmed, Tarek Ben, Caron, Olivier, Busson, Pierre, Boulate, David, Deschasaux-Tanguy, Mélanie, Arnault, Nathalie, Pol, Jonathan G, Piaggio, Eliane, Touvier, Mathilde, Zitvogel, Laurence, Delaloge, Suzette, Martins, Isabelle, Kroemer, Guido
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.09.2024; BioMed Central; BMC
• Subjects: Animals; Biomarkers, Tumor; Breast Neoplasms - diagnosis; Breast Neoplasms - immunology; Cancer; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Chemotherapy; Development and progression; Diagnosis; Diazepam; Drug therapy; Ethylenediaminetetraacetic acid; Female; Gene mutations; Health aspects; Humans; Immunologic Surveillance; Immunosurveillance; Immunotherapy; Life Sciences; Lung cancer, Non-small cell; Lung Neoplasms - diagnosis; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Mice; Monoclonal antibodies; Neoplasms - diagnosis; Neoplasms - etiology; Neoplasms - immunology; Neuroendocrine factors; Non-small cell lung cancer; Precocious detection; Protein binding; Risk Factors; RNA sequencing; Sarcoma; T cells; Thiols; Tumor proteins; Precocious detection; Immunosurveillance; Neuroendocrine factors; Immunotherapy; Non-small cell lung cancer
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-024-02098-5

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.