The Crosstalk Between CTNNB1 Mutation and M2 Macrophages Contribute to Hepatocellular Carcinoma Suppressive Immune Microenvironment

Objective: Mutations in the CTNNB1 gene was the second most common mutation after TP53 in HCC. However, the CTNNB1 mutation and tumor immune microenvironment of HCC have not been clarified. Materials: and Methods: We compared the CTNNB1 mutation frequency and hotspot site in China Pan-cancer (OrigiMed2020) and TCGA PanCancer Atlas cohort via cBioPortal database. The differentially expressed genes and corresponding function enrichment analysis between CTNNB1 mutation and non-mutation was detected by DESeq2 and MetaScape database, respectively. We also analyzed the association between CTNNB1 mutation status and drug sensitivity based on the RNAactDrug and DREIMT database. Furthermore, we explored the genetic alteration score, infiltration of immune cell, and response to immune checkpoint inhibitor therapy under CTNNB1 mutation status by means of IPS and TIDE methods. Besides, gene module associated with CTNNB1 mutation and M2 immune cell were identified by weighted gene co-expression network analysis (WGCNA). Besides, we integrated differently expressed genes and gene modules associated crosstalk CTNNB1 mutation and M2 immune cell to seek targeted genes for CTNNB1-mutated HCC. Results: : There are obvious differences in CTNNB1 mutation frequency and mutation hotspots between European-American and Chinese patients with HCC. CTNNB1 mutation significantly altered Wnt signaling pathway score and he sensitivity to drugs, such as Nutlin-3 and PHA-665752. High TMB, microsatellite instability, neoantigen loads, intratumor heterogeneity score, number of segments, and homologous recombination defects score were significantly increased in CTNNB1 mutations group. Besides, Cibersort, EPIC, quantiseq, and xcell immune method suggested M2-type macrophages are significantly enriched in CTNNB1-mutated HCC. Interestingly, CTNNB1-mutated HCC showed a low level in immune checkpoint signature score. 11 gene modules were identified by WGCNA. Of them, we focused on MEmagenta (Gene modules positively correlated to CTNNB1 mutation and M2 macrophage) and MEbrown gene module (Gene modules negatively correlated to CTNNB1 mutation and M2 macrophage). Targeting pathways such as Wnt signaling and leukocyte activation were promising therapeutic strategy for CTNNB1-mutant HCC. Conclusion: CTNNB1 plays an important role in the initiation and progression of HCC. Our results may provide novel insights for the selection of immunotherapeutic targets and prognostic biomarkers fo r CTNNB1-mutant HCC.