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

Genes & Immunity volume 25, pages 307–316 (2024)Cite this article

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Abstract

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.

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Fig. 1: Clinical course, radiologic images and pathological characteristics before and after PARPi and ICI combination treatment.
Fig. 2: The different expression genes between high and low PBscore group.
Fig. 3: PBscore may remodel the immune microenvironment of GBC.
Fig. 4: Changes of immune microenvironment before and after PARPi and ICI combination treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. The data that support the results of current study is available on The Cancer Genome Atlas (TCGA) websites.

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Acknowledgements

We would like to thank the patient and her family for their understanding.

Funding

This study was funded by the National Natural Science Foundation of China. (No. 82274606) and the Fund of Nature Science Foundation of Hunan Province (No. 2023JJ30876).

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Authors and Affiliations

  1. Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China

    Yu Chen, Xudong Fan, Shan Zeng & Pingping Gan

  2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China

    Yu Chen, Xudong Fan, Shan Zeng & Pingping Gan

  3. Department of Stomatology, Third Xiangya Hospital, Central South University, Changsha, 410008, China

    Ruohuang Lu

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Contributions

Y Chen and XD Fan were responsible for the overall design of the study, processing of bioinformatics data, experimental validation, and writing of the manuscript, S Zeng and RH Lu analyzed data. PPGan was responsible for the statistical work towards experimental data and revised the full text. All authors read and approved the final manuscript.

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Correspondence to Pingping Gan.

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The authors declare no competing interests.

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The experiment of the study was approved by the Medical Ethics Committee of Xiangya Hospital of Central South University (202109013). All procedures were conducted according to the Declaration of Helsinki. Written informed consent was obtained from the patient’s husband for publication of the details of her medical case and any accompanying images.

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Chen, Y., Fan, X., Lu, R. et al. PARP inhibitor and immune checkpoint inhibitor have synergism efficacy in gallbladder cancer. Genes Immun 25, 307–316 (2024). https://doi.org/10.1038/s41435-024-00280-9

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