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

Abstract

Background Gallbladder cancer (GBC) is aggressive with poor prognosis. PARP inhibitors (PARPi) targets PARP enzymes, showing efficacy in BRCA-mutated patients. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has transformed cancer treatment. Yet, the combined impact of PARPi and ICIs in GBC is unclear. Methods We presented a groundbreaking case of a GBC patient with BRCA2 mutations receiving PARPi and ICIs combination therapy after failing multiple-line treatments. NGS-Seq identified BRCA gene mutations. To further investigate the 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 BRCA gene WT/mutation patients. Results A BRCA2-mutated GBC patient achieved a remarkable 31-month response to the combination therapy of PARPi and ICIs. RNA-Seq analysis revealed the correlations between PBscore and the levels of immune checkpoints, tumor-infiltrating immune cells (TIICs) and its crucial role in the cancer-immunity cycle. Multiplexed immunofluorescence imaging validated the activation of the tumor microenvironment. Furthermore, as the drug resistance, we observed an upregulation of negative immune checkpoints such as CEACAM1, which indicate multiple ICIs may enhance the efficacy of the therapy. Conclusion Our study advances understanding of synergistic PARPi-ICI effects in GBC, offering a promising alternative for BRCA2-mutated patients. However, to solidify its clinical applicability, further validation with a large sample size is needed.