Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
J Immunother Cancer. 2023 Jan;11(1). doi: 10.1136/jitc-2022-005627.
Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.
PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated by co-culture experiments and by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.
In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.
We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.
聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）在 BRCA 突变型卵巢癌患者中显示出强大的治疗效果。然而，获得性 PARPi 耐药仍然是临床的主要挑战。
通过在同源 BRCA1 缺陷型卵巢肿瘤中进行奥拉帕利的长期治疗，生成 PARPi 耐药卵巢癌小鼠模型。通过共培养实验和对人源和鼠源 PARPi 耐药肿瘤的肿瘤微环境（TME）中的免疫细胞进行分析，研究信号转导和转录激活因子 3（STAT3）介导的免疫抑制作用。对 TME 中的髓样细胞进行全基因组转录组分析，以评估 STING（干扰素基因刺激物）激动剂对 PARPi 耐药卵巢肿瘤的抗肿瘤免疫调节作用。使用 STING 激动剂克服 STAT3 介导的免疫抑制和同源和患者来源的异种移植卵巢癌模型中的获得性 PARPi 耐药。
在这项研究中，我们揭示了肿瘤相关巨噬细胞（TAMs）在 TME 中对 PARP 抑制的适应性耐药机制。在小鼠模型和患者中，BRCA 缺陷型卵巢肿瘤中发现了明显增加的促肿瘤巨噬细胞群体，这些肿瘤对 PARPi 产生了耐药性。从机制上讲，PARP 抑制会增加肿瘤细胞中的 STAT3 信号通路，进而促进 TAMs 的促肿瘤极化。肿瘤细胞中 STAT3 的消融减轻了促肿瘤巨噬细胞的极化，并增加了 PARP 抑制时肿瘤浸润的 T 细胞。在患者来源的 PARPi 耐药 BRCA1 突变型卵巢肿瘤中证实了这些发现。重要的是，STING 激动剂通过重塑免疫抑制性 TME 并克服卵巢癌中 TME 依赖性适应性耐药来重新编程髓样细胞。这种效应通过添加程序性细胞死亡蛋白 1 阻断进一步增强。
我们阐明了一种适应性免疫抑制机制，导致 BRCA1 突变型卵巢肿瘤对 PARPi 的耐药性。这是通过 PARPi 诱导的肿瘤细胞中 STAT3 激活促进促肿瘤 TAMs 的富集介导的。我们还提供了一种使用 STING 激动剂重塑免疫抑制性 TME 并克服卵巢癌中 PARPi 耐药的新策略。
