Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
Genes Immun. 2024 Aug;25(4):307-316. doi: 10.1038/s41435-024-00280-9. Epub 2024 Jun 12.
Gallbladder cancer (GBC) is an aggressive cancer with poor prognosis. PARP inhibitors (PARPi) target PARP enzymes and have shown efficacy in patients with breast cancer gene (BRCA) mutations. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has transformed cancer treatment. However, the combined impact of PARPi and ICIs in GBC remains unclear. We present a groundbreaking case of a GBC patient with BRCA2 mutations who received combination therapy with PARPi and ICIs after failing multiple lines of treatment. Next-generation sequencing (NGS-Seq) identified BRCA gene mutations. To further investigate potential mechanisms, we developed a PARP1-BRCA1-BRCA2 pathway-related risk score (PBscore) system to evaluate the impact of PARPi on the tumor immune microenvironment via RNA-Seq data. Gene expression and functional analysis identified potential mechanisms associated with the PBscore. Experimental validation assessed the impact of the combination therapy on the tumor microenvironment using multiplexed immunofluorescence imaging and immunohistochemistry in patients with BRCA gene wild type or mutations. RNA-Seq analysis revealed correlations between PBscore, immune checkpoint levels, tumor-infiltrating immune cells (TIICs), and the cancer-immunity cycle. Multiplexed immunofluorescence imaging validated that low PBscore patients might have an active tumor microenvironment. Furthermore, upon drug resistance, we observed an upregulation of negative immune checkpoints such as CEACAM1, indicating that the tumor immune microenvironment becomes suppressed after resistance. Our study revealed that PBscore could serve as a biomarker to predict immunotherapy efficacy, offering a promising alternative for BRCA2-mutated GBC patients.
胆囊癌（GBC）是一种侵袭性强、预后差的癌症。聚腺苷二磷酸核糖聚合酶（PARP）抑制剂（PARPi）靶向 PARP 酶，在乳腺癌基因（BRCA）突变患者中显示出疗效。免疫疗法，特别是免疫检查点抑制剂（ICI），已经改变了癌症治疗的格局。然而，PARPi 和 ICI 联合应用于 GBC 的综合影响尚不清楚。我们报告了一个突破性的病例，一名 BRCA2 基因突变的 GBC 患者在多次治疗失败后接受了 PARPi 和 ICI 的联合治疗。下一代测序（NGS-Seq）确定了 BRCA 基因突变。为了进一步探讨潜在的机制，我们开发了一个 PARP1-BRCA1-BRCA2 通路相关风险评分（PBscore）系统，通过 RNA-Seq 数据评估 PARPi 对肿瘤免疫微环境的影响。基因表达和功能分析确定了与 PBscore 相关的潜在机制。实验验证通过对 BRCA 基因野生型或突变患者的肿瘤进行多重免疫荧光成像和免疫组化分析，评估了联合治疗对肿瘤微环境的影响。RNA-Seq 分析揭示了 PBscore 与免疫检查点水平、肿瘤浸润免疫细胞（TIICs）和癌症免疫循环之间的相关性。多重免疫荧光成像验证了低 PBscore 患者可能具有活跃的肿瘤微环境。此外，在耐药后，我们观察到负性免疫检查点如 CEACAM1 的上调，表明肿瘤免疫微环境在耐药后受到抑制。我们的研究表明，PBscore 可以作为预测免疫治疗疗效的生物标志物，为 BRCA2 突变的 GBC 患者提供了一种有前途的治疗选择。
