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

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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

Edité par CCSD ; BioMed Central -

International audience. Background: 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.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: 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: 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.

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