Bound Nirashaa T, Vandenberg Cassandra J, Kartikasari Apriliana E R, Plebanski Magdalena, Scott Clare L
Cancer Biology and Stem Cells, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Cancer Ageing and Vaccines (CAVA), Translational Immunology & Nanotechnology Research Program, School of Health & Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.
Front Genet. 2022 Sep 9;13:886170. doi: 10.3389/fgene.2022.886170. eCollection 2022.
High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., 2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure.
高级别浆液性卵巢癌（HGSOC）是一种基因组不稳定的恶性肿瘤，占卵巢癌所致所有死亡病例的70%以上。大约50%的HGSOC在同源重组（HR）DNA修复途径中存在缺陷（例如，2个突变），聚腺苷酸二磷酸核糖聚合酶抑制剂（PARPi）的引入显著改善了HR缺陷型HGSOC女性患者的预后。通过阻断已经缺乏高保真HR途径的癌细胞中单链DNA损伤的修复，PARPi会导致双链DNA断裂的积累，从而导致细胞死亡。因此，这种合成致死性导致PARPi选择性地靶向癌细胞，产生令人瞩目的疗效。尽管如此，对PARPi的耐药性通常通过多种机制产生，例如获得继发性突变。也许记录较少的是，PARPi可通过上调干扰素基因（STING）途径、上调免疫检查点如PD-L1以及刺激促炎细胞因子的产生，影响肿瘤微环境和免疫反应。虽然靶向免疫疗法尚未在HGSOC的临床治疗中找到立足之地，但上述证据以及正在探索PARPi与免疫药物（包括免疫检查点抑制剂）协同作用的研究表明，在HGSOC中靶向免疫反应具有潜力。此外，将PARPi与表观遗传调节药物联合使用可能会提高PARPi的疗效，通过诱导BRCA缺陷表型使耐药癌细胞对PARPi敏感。最后，在PARPi治疗期间激活免疫反应可能会引发抗癌免疫反应，增强疗效并减轻PARPi耐药性的发展。在此，我们将回顾新兴的PARPi文献，重点关注PARPi对HGSOC免疫反应的影响以及表观遗传联合疗法的潜力。我们强调将HGSOC从致命疾病转变为慢性疾病并提高治愈可能性的潜力。
