Guanylate-Binding Protein 1 as a Potential Predictor of Immunotherapy: A Pan-Cancer Analysis

Background: Mainstream application of cancer immunotherapy is hampered by the low response rate of most cancer patients. A novel immunotherapeutic target or a biomarker predicting response to immunotherapy needs to be developed. Guanylate-binding protein 1 (GBP1) is an interferon (IFN)-inducible guanosine triphosphatases (GTPases) involving inflammation and infection. However, the immunological effects of GBP1 in pan-cancer patients are still obscure. Methods: Using large-scale public data, we delineated the landscape of GBP1 across 33 cancer types. The correlation between GBP1 expression or mutation and immune cell infiltration was estimated by ESTIMATE, TIMER, xCell, and quanTIseq algorithms. GBP1-related genes and proteins were subjected to function enrichment analysis. Clustering analysis explored the relationship between GBP1 expression and anti-tumor immune phenotypes. We assessed the patient's response to immunotherapy using the tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS). Furthermore, we validated the predictive power of GBP1 expression in four independent immunotherapy cohorts. Results: GBP1 was differentially expressed in tumors and normal tissues in multiple cancer types. Distinct correlations existed between GBP1 expression and prognosis in cancer patients. GBP1 expression and mutation were positively associated with immune cell infiltration. Function enrichment analysis showed that GBP1-related genes were enriched in immune-related pathways. Positive correlations were also observed between GBP1 expression and the expression of immune checkpoints, as well as tumor mutation burden (TMB). Pan-cancer patients with higher GBP1 expression were more inclined to display "hot" anti-tumor immune phenotypes and had lower TIDE scores and higher immunophenoscore, suggesting that these patients had better responses to immunotherapy. Patients with higher GBP1 expression exhibited improved overall survival and clinical benefits in immunotherapy cohorts, including the Gide et al. cohort [area under the curve (AUC): 0.813], the IMvigor210 cohort (AUC: 0.607), the Lauss et al. cohort (AUC: 0.740), and the Kim et al. cohort (AUC: 0.793). Conclusion: This study provides comprehensive insights into the role of GBP1 in a pan-cancer manner. We identify GBP1 expression as a predictive biomarker for immunotherapy, potentially enabling more precise and personalized immunotherapeutic strategies in the future.