自噬抑制组织激素DBI/ACBP的中和（地西爱结合抑制剂，酰基-COA结合蛋白）增强了抗癌免疫监视
Neutralization of the autophagy-repressive tissue hormone DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) enhances anticancer immunosurveillance
影响因子:14.30000
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
摘要
随着衰老和体重指数（BMI）（BMI）的增加，大噬菌/自噬抑制剂DBI/ACBP的血浆浓度（地西epaN结合抑制剂，酰基-COA结合蛋白）会增加。高龄和肥胖是癌症发展的最重要危险因素之一。我们观察到，由于BRCA1，BRCA2和TP53突变引起的癌症易感性综合征患者表现出异常高血浆DBI/ACBP水平。此外，与保持无癌症的年龄和BMI匹配的对照相比，没有已知癌症易感性综合征的患者在癌症诊断之前（0-3岁）也表现出更高的DBI/ACBP水平。因此，超级血浆DBI/ACBP构成了后来癌症发展的危险因素。小鼠实验表明，遗传或抗体介导的DBI/ACBP抑制会延迟癌症的发展或进展。在化学免疫性疗法的背景下，DBI/ACBP中和可以通过非排量效应T细胞增强肿瘤浸润，但通过调节性T细胞降低浸润。这导致了乳腺癌，非小细胞肺癌和肉瘤模型的更好控制。我们得出的结论是，DBI/ACBP构成了一个可起作用的自噬检查站，用于改善癌症免疫监视。缩写：BMI，体重指数； CTL，细胞毒性T淋巴细胞； DBI，地西爱结合抑制剂，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1; SCRNA-SEQ，单细胞RNA测序； Treg，调节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.