中和自噬抑制性组织激素DBI/ACBP（地西泮结合抑制剂，酰基-CoA结合蛋白）增强抗癌免疫监视的作用
Neutralization of the autophagy-repressive tissue hormone DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) enhances anticancer immunosurveillance
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影响因子:14.3
分区:生物学1区 Top / 细胞生物学2区
发表日期:2024 Dec
作者:
Léa Montégut, Isabelle Martins, Guido Kroemer
DOI:
10.1080/15548627.2024.2411854
摘要
血浆中宏自噬/自噬抑制剂DBI/ACBP（地西泮结合抑制剂，酰基-CoA结合蛋白）的浓度随年龄增长和身体质量指数（BMI）升高而增加。年龄增长和肥胖均是癌症发生的最重要风险因素之一。我们观察到，由BRCA1、BRCA2和TP53突变引起的癌症易感综合征患者血浆DBI/ACBP水平异常升高。此外，在即将诊断出癌症（0-3年内）的患者中，即使没有已知的癌症易感综合征，也表现出较高的DBI/ACBP水平，与年龄和BMI匹配的未发生癌症的对照组相比亦如此。因此，血浆中超常的DBI/ACBP水平构成了后来癌症发展的风险因素。小鼠实验显示，遗传或抗体介导的DBI/ACBP抑制可以延缓癌症的发生或进展。在化疗免疫治疗的背景下，DBI/ACBP中和增强了非耗竭效应T细胞的肿瘤浸润，同时减少了调节性T细胞的浸润，导致乳腺癌、非小细胞肺癌和肉瘤模型中的癌症控制效果更佳。我们得出结论，DBI/ACBP构成了一个可操作的自噬检查点，有助于改善癌症免疫监视。缩写：BMI，身体质量指数；CTL，细胞毒性T淋巴细胞；DBI，地西泮结合抑制剂，酰基-CoA结合蛋白；mAb，单克隆抗体；NSCLC，非小细胞肺癌；PDCD1/PD-1，程序性细胞死亡蛋白1；scRNA-seq，单细胞RNA测序；Treg，调节性T细胞。
Abstract
The plasma concentration of the macroautophagy/autophagy inhibitor DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) increases with aging and body mass index (BMI). Both advanced age and obesity are among the most important risk factors for the development of cancer. We observed that patients with cancer predisposition syndromes due to mutations in BRCA1, BRCA2 and TP53 exhibit abnormally high plasma DBI/ACBP levels. Additionally, patients without known cancer predisposition syndromes also manifest higher DBI/ACBP levels before imminent cancer diagnosis (within 0-3 years) as compared to age and BMI-matched controls who remain cancer-free. Thus, supranormal plasma DBI/ACBP constitutes a risk factor for later cancer development. Mouse experimentation revealed that genetic or antibody-mediated DBI/ACBP inhibition can delay the development or progression of cancers. In the context of chemoimmunotherapy, DBI/ACBP neutralization enhances tumor infiltration by non-exhausted effector T cells but reduces infiltration by regulatory T cells. This resulted in better cancer control in models of breast cancer, non-small cell lung cancer and sarcoma. We conclude that DBI/ACBP constitutes an actionable autophagy checkpoint for improving cancer immunosurveillance. Abbreviation: BMI, body mass index; CTL, cytotoxic T lymphocyte; DBI, diazepam binding inhibitor, acyl-CoA binding protein; mAb, monoclonal antibody; NSCLC, non-small cell lung cancer; PDCD1/PD-1, programmed cell death 1; scRNA-seq, single-cell RNA sequencing; Treg, regulatory T cell.