Endocrine Abstracts

Context: Adrenocortical carcinoma (ACC) are endocrine malignant neoplasms associated with severe aggressiveness. Tumour-related glucocorticoid excess occurs in 60% of patients and is associated with poor prognosis. First clinical trials using immune checkpoint inhibitors are quite unsatisfactory and treatment advancements are urgently needed.

Recently, we characterized tumour-infiltrating lymphocytes (TILs) in ACC and identified the detrimental dependency of immunosuppressive effects of glucocorticoids. In this study, we analyse the impact of the checkpoint markers programmed-death 1 (PD1) and its ligand PD-L1 on patients´ outcome and treatment response as additional factor on resistance to immunotherapy.

Methods: We performed immunofluorescence analysis quantifying the expression of the checkpoint marker PD-1 and PD-L1 in 58 primary ACC. Furthermore, we correlated its presence with clinical data.

Results: Most ACCs show infiltrates of T-cells (86.3%, 7.65 cells/HPF) both cytotoxic (84.3%, 5.70 cells/HPF) and helper cells (74.0%, 6.68 cells/HPF) and Tregs (49.3%, 0.75 cells/HPF). Interestingly, the CD3⁺, CD4⁺ and CD8⁺ ACC-infiltrating immune cells were associated with better overall survival (HR for death: 0.45, 95% CI : 0.25–0.87, P = 0.016; 0.47; 95% CI : 0.23–0.67, P = 0.001; 0.39; 95% CI : 0.26–0.85, P = 0.013; respectively). Moreover, T helper cells were negatively correlated with glucocorticoid excess in localized, non-metastatic ACC and even in local recurrences and metastases (P = 0.049 and P = 0.006; respectively). In addition, 36% of ACC show intra-tumoral expression of PD-1 positive tumour-infiltrated lymphocytes (15 ± 30 cells/HPF), while 83% (34 ± 82 cells/HPF) of ACC tumour cells were positive for PD-L1. Interestingly, all tumours with PD-1/PD-L1 expression correlated with immunosuppressive glucocorticoid excess and thus were in the poor prognosis group characterized by immune depletion.

Conclusion: First, tumours of ACC patients are characteristically infiltrated by CD3⁺, CD4⁺ and CD8⁺ T cells that positively influence patients’ overall survival. However, ACC were less infiltrated by CD4⁺ T cell in presence of glucocorticoids. Second, ACC tumours often have increased, but heterogeneous expression of immune checkpoint molecule PD-1/PD-L1 on tumoural and infiltrating immune cells predominantly under glucocorticoid excess conditions. Hence, examine the molecular checkpoint markers considering glucocorticoid secretion may be an option in order to predict patients´ outcome and treatment response to immunotherapy.