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

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.

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.

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).

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.