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Exploring Immune-Related Gene Signatures for Prognostic Modeling and Immunotherapy Guidance in Gallbladder Cancer
Gallbladder cancer (GBC), a rare and aggressive malignancy, is substantially less explored than other cancers, and particularly its immune landscape has not been fully characterized. This study proposes to discover immune-related signatures, build a robust prognostic model, and guide immunotherapy for GBC. It performed differential expression analysis on transcriptomic data from TCGA-GBC (RNA-seq) and GSE139902 (microarray) datasets, and found a total of 4,312 and 1,125 significantly differentially expressed genes (DEGs), respectively. Among these, 96 DEGs overlapped with known immune-associated markers. Univariate Cox regression revealed 18 survival-related immune genes, including LAMP3 (HR=1.78, 95% CI: 1.42-2.24, p=1.2E-05). Multivariate analysis refined the model to five immune-related genes: LAMP3 (HR=1.78, 95% CI: 1.42-2.24, p=1.2E-05), IDO1 (HR=1.56, 95% CI: 1.23-1.98, p=2.3E-04), CCL4 (HR=1.45, 95% CI: 1.15-1.83, p=0.0018), CD276 (HR=0.72, 95% CI: 0.56-0.93, p=0.0046), and CXCL8 (HR=1.32, 95% CI: 1.06-1.65, p=0.012), where CD276 was identified as a protective factor.
The model showed robust predictive performance, with AUCs of 0.796, 0.783, and 0.762 for 1-, 3-, and 5-year overall survival in TCGA-GBC, and 0.815, 0.788, and 0.764 in the independent GSE168453 dataset. Furthermore, TIDE and SubMap analysis indicated that high-risk patients had a higher response rate to anti-PD1 therapy (40.2% vs. 29.8%, p<0.05), with high-risk patients more sensitive to anti-CTLA4 and low-risk patients to anti-PD1. Functional enrichment showed these genes are involved in immune checkpoint regulation, antigen processing, and inflammatory response. These findings demonstrate the utility of immune-related gene signatures for prognostic modeling and therapeutic decision-making in GBC.1.Cheng Z, Yang C, Zhao Q, Zhong J, Zhang J, Jin R, Li Y, Ta N, Wu D, Yuan Z, Sun W, Wang R. Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer. Cancer Sci. 2024 Jun;115(6):1979-1988.
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