Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Present address: Department of Internal Medicine, New York University Grossman School of Medicine, New York, NY, USA.
Mol Cancer. 2024 Oct 30;23(1):242. doi: 10.1186/s12943-024-02147-z.
Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined.
We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies.
We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i.
Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.
除了 PDL1 作为肿瘤表面表达的免疫检查点分子的典型作用外，肿瘤内在的 PDL1 信号还调节调节治疗耐药性的非典型免疫病理途径，其意义、机制和治疗靶点仍不完全清楚。最近的报告表明，肿瘤内在的 PDL1 信号参与 DNA 损伤反应（DDR），包括促进同源重组 DNA 损伤修复和 DDR 蛋白的 mRNA 稳定性，但许多机制细节尚不清楚。
我们从可移植的小鼠和人类癌细胞系中遗传缺失 PDL1，以了解肿瘤内在的 PDL1 信号在 DNA 损伤反应中的后果。我们用原发性人类肿瘤和诱导型小鼠肿瘤的研究补充了这项工作。我们开发了新的方法来显示特定亚细胞位置的肿瘤内在的 PDL1 信号。我们用重新利用 FDA 批准的药物在小鼠模型中体内耗尽肿瘤 PDL1，进行概念验证的临床转化研究。
我们表明，肿瘤内在的 PDL1 促进了检查点激酶-2（Chk2）介导的 DNA 损伤反应。细胞内而不是表面表达的 PDL1 通过拮抗 PIRH2 E3 连接酶介导的 Chk2 多泛素化和蛋白降解，在翻译后水平和独立于 PD1 控制 Chk2 蛋白含量。肿瘤遗传缺失 PDL1 特异性降低肿瘤 Chk2 含量，但不降低 ATM、ATR 或 Chk1 DDR 蛋白，增强体外不同人类和小鼠肿瘤模型中 Chk1 抑制剂（Chk1i）的合成致死性，并提高体内 Chk1i 的疗效。用头孢吡肟或头孢他啶进行肿瘤 PDL1 的药理学耗竭，通过降低肿瘤 Chk2、以肿瘤 PDL1 依赖的方式诱导 Chk1i 的合成致死性，并与 Chk1i 联合使用时减少体内肿瘤生长，复制了肿瘤遗传缺失 PDL1 的作用。
我们的数据挑战了普遍的表面 PDL1 范式，阐明了肿瘤内在的 PDL1 在调节 ATM/Chk2 DNA 损伤反应轴和 E3 连接酶介导的蛋白降解方面的重要和以前未被认识到的作用，提示肿瘤 PDL1 作为 Chk1i 疗效的生物标志物，并支持药理学肿瘤 PDL1 耗竭的快速临床潜力，以治疗选定的癌症。
