PARP inhibitor and immune checkpoint inhibitor have synergism efficacy in gallbladder cancer

• Published in: Genes and immunity 2024-08, Vol.25 (4), p.307-316
• Main Authors: Chen, Yu, Fan, Xudong, Lu, Ruohuang, Zeng, Shan, Gan, Pingping
• Format: Article
• Language: English
• Subjects: 14; 14/5; 38; 38/91; 631/208; Biomedical and Life Sciences; Biomedicine; BRCA1 protein; BRCA2 protein; Breast cancer; Cancer Research; Cancer therapies; CD66 antigen; CEACAM1 protein; Combination therapy; Drug resistance; Enzyme inhibitors; Gallbladder cancer; Gene Expression; Human Genetics; Immune checkpoint inhibitors; Immunofluorescence; Immunohistochemistry; Immunology; Immunotherapy; Mutation; Next-generation sequencing; Point mutation; Poly(ADP-ribose) polymerase; Targeted cancer therapy; Tumor microenvironment; Tumor-infiltrating lymphocytes
• ISSN: 1476-5470; 1466-4879; 1476-5470
• DOI: 10.1038/s41435-024-00280-9

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.