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Benzodiazepines compromise the outcome of cancer immunotherapy


. 2024 Oct 7;13(1):2413719.


doi: 10.1080/2162402X.2024.2413719.


eCollection 2024.

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Léa Montégut et al.


Oncoimmunology.


.

Abstract

Acyl CoA binding protein (ACBP, which is encoded by diazepam binding inhibitor, DBI) acts on the gamma-amino butyric acid (GABA) receptor type A via a specific binding site that is shared by diazepam and other benzodiazepines. Both ACBP/DBI and benzodiazepines act as positive allosteric modulators, hence increasing GABA effects on this receptor. Recently, we found that ACBP/DBI acts as an endogenous immunosuppressor, meaning that its antibody-mediated neutralization has immunostimulatory effects and enhances the efficacy of immunotherapy and chemoimmunotherapy in mouse models. Driven by these considerations, we investigated whether diazepam administration in mice would reverse the beneficial effects of ACBP/DBI neutralization on cancer chemoimmunotherapy. Indeed, diazepam abolished the therapeutic of anti-ACBP/DBI antibodies, supporting the idea that diazepam exerts immunosuppressive properties. Of note, treatment with benzodiazepines was associated with poor clinical responses to chemoimmunotherapy in patients with non-small cell lung cancer (NSCLC) as compared to individuals not receiving any psychotropic drugs. Medication with other psychotropic drugs than benzodiazepines did not compromise the outcome of chemoimmunotherapy, indicating that this immunosuppressive effect was benzodiazepine specific. We conclude that benzodiazepines may confer systemic immunosuppression. This hypothesis requires further epidemiological and clinical confirmation.


Keywords:

Benzodiazepines; Immunotherapy; comedications; neuroendocrine factors; non-small cell lung cancer.

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Conflict of interest statement

IM is a consultant for Osasuna Therapeutics. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results.

Figures


Figure 1.



Figure 1.

Negative effects of diazepam on immunochemotherapy in mice. Following the schedule of cancer cell inoculation and drug administration to C57BL/6J mice depicted in the scheme (a), the effect of various treatments regimens on the growth of MCA205 fibrosarcomas was assessed. Results are shown as mean tumor size ± standard error of the mean (b) and Kaplan-Meyer plots of the animal survival (c). P-values corresponding to the pairwise comparisons among treatment groups are displayed in a matrix (d). Tumor growth rates were compared with the TumGrowth tool (https://kroemerlab.Shinyapps.io/TumGrowth) by linear mixed effect modeling. Survival differences were tested using log-rank (mantel-cox) test. ACBP: acyl coA binding protein (ACBP/DBI); CT: chemotherapy; PD-1: programmed cell death protein 1.


Figure 2.



Figure 2.

Benzodiazepines and the endozepine ACBP/DBI share a poor prognosis effect in non-small cell lung cancer patients. Kaplan-Meier curves of non-small cell lung cancer (NSCLC) patients included in the ONCOBIOTICS and CRCHUM lung cancer biobank observational studies on comedications demonstrate that the use of benzodiazepines (BZD) during therapy has a negative effect on progression-free survival (PFS, a) and a trend for worsening overall survival (OS, b). These effects were not observed with other psychiatric comedications (PSY not BZD). Circulating levels of ACBP/DBI were quantified by ELISA in the plasma from patients with NSCLC participating to the CRCHUM study (c, N = 121 patients with available plasma for ACBP measurements). Survival datasets are displayed as Kaplan-Meier curves and were compared by log-rank Mantel-Cox test, plasma concentrations were compared overall across the three groups by Kruskal-Wallis test.

References

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Grants and funding

The work was supported by the Agence Nationale de la Recherche Association pour la Recherche sur le Cancer Cancéropôle Ile de France Fondation pour la Recherche Médicale HORIZON EUROPE European Research Council Institut National Du Cancer Institut Universitaire de France Labex Immuno-Oncology Ligue Contre le Cancer Hevolution Network on Senescence and Aging Elior EJPRD Mark foundation Seerave Foundation.


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