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J Immunother Cancer ; 8(1)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32474412


BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in ~60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy. METHODS: We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3+), T helper cells (CD3+CD4+), cytotoxic T cells (CD3+CD8+) and regulatory T cells (Tregs; CD3+CD4+FoxP3+) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess). RESULTS: 86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4+- and CD8+ subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess). CONCLUSION: Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.

J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449514


CONTEXT: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. OBJECTIVE: To investigate SOAT1 protein expression as a marker of treatment response to mitotane. PATIENTS: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. SETTING: Retrospective study at 12 ACC referral centers. MAIN OUTCOME MEASURE: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. CONCLUSIONS: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

Cell Death Dis ; 11(3): 192, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184394


Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an iron-dependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC50 values of 5.7 × 10-8, 8.1 × 10-7 and 2.1 × 10-8 M, respectively, while all non-steroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.