β-Catenin-driven adrenocortical carcinoma is characterized with immune exclusion

Abstract

Aim: Adrenocortical carcinoma (ACC) is characterized by overexpressed CTNNB1, which is reported to modulate immune exclusion. Cross talk between CTNNB1 and cancer immunity in ACC remains unclear. Materials and methods: In silico reproduction of TCGA-ACC dataset (N = 92) and external validation using tissue samples were performed (N = 16). Expression data of CTNNB1, PD-1, and PD-L1 were extracted in silico and tumor-infiltrating lymphocytes (TILs) were profiled using code provided by Tumor IMmune Estimation Resource (TIMER). In-house formalin-fixed paraffin-embedded ACC samples were processed using immunohistochemical (IHC) staining for CTNNB1, CD45, PD-1, and PD-L1. Results: Increased CTNNB1 expression was significantly associated with worsened overall survival (OS) (P = 0.006). CD8+ cells were significantly associated with better OS (P = 0.02). Higher PD-L1 (P = 0.019), but not PD-1 expression (P = 0.325), was associated with better OS. CTNNB1 overexpression was significantly associated with increased tumor purity (r = 0.356, P = 0.002) and fewer TILs (r = -0.833, P = 0.029), decreased infiltrating CD8+ cells (P = 0.033), and increased infiltrating B cells (P = 0.026). CTNNB1 expression was negatively correlated with PD-L1 expression (r = -0.308, P = 0.006) but not with PD-1 expression (P = 0.067), which were externally validated (P = 0.032 for PD-L1 and P = 0.400 for PD-1). The Cox regression model encompassing gender, B cells, CD8+ cells, PD-L1, CTNNB1, and Ki-67 revealed that only Ki-67 overexpression remained significantly associated with OS (P˂ 0.001), while CTNNB1 showed marginal significance (P = 0.06). CTNNB1-overexpressed patients were more likely to have cortisol excess (P = 0.003). Conclusion: ACC with CTNNB1 overexpression is associated with poor prognosis and decreased immunity. Our findings suggest that CTNNB1-targeting therapy may overcome immune exclusion in ACC.