Endocrine Abstracts

Adrenocortical carcinoma (ACC) is a very severe endocrine malignancy with poor prognosis. While cancer immunotherapies have revolutionized the treatment of several cancer entities, the results of initial studies of different immune checkpoint inhibitors in ACC were heterogeneous and clinically substantial responses were observed only in a subset of patients. Expression of immune checkpoint molecules - programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T Lymphocytes-associated protein 4 (CTLA-4) - has been shown to predict response in different, but not all cancer entities. Using immunohistochemistry, a cohort of 129 ACCs was examined for PD-1, PD-L1 and CTLA-4 expression. PD-1, PD-L1 and CTLA-4 were present (threshold of ≥1% of cells) in 17.4%, 24.4% and 67.8% of samples, respectively, but expression was heterogeneous and in general rather low for PD-1 and PD-L1 (median 3.9% (range 1-15), 19.7% (range 1-90)) and more present for CTLA-4 (median 36.8% (range 1-90)). Interestingly, PD-1 expression was significantly associated with beneficial progression-free (HR: 0.30, 95% CI 0.13-0.72) and overall survival (HR: 0.21, 95% CI 0.53-0.84) independently of established prognostic factors, including ENSAT tumor stage, resection status, Ki67 proliferation index and glucocorticoid excess. In contrast, its ligand PD-L1 and CTLA-4 were not associated with clinical outcome in this ACC cohort. In addition, we analyzed the correlation of PD-1 and PD-L1 with tumor-infiltrating lymphocytes. Whereas PD-L1 correlated significantly with the number of CD3⁺-, CD8⁺-, and FoxP3⁺ T cells (p = 0.0003, < 0.0001 and < 0.0001, respectively), PD-1 correlated only with FoxP3⁺ T cells (p = 0.020). When including both PD-1 and different T cell subtypes in the above-mentioned multivariate Cox regression, the presence of PD1⁺ cells was the strongest predictor of favorable clinical outcome. In conclusion, this study provides several potential explanations for the heterogeneous results of the immune checkpoint therapy in advanced ACC. In addition, PD-1 expression serves as a strong prognostic biomarker that can easily be applied in routine clinical care as part of histo-pathological assessment.