Weigand Isabel, Triebig Alexandra S, Maier Tanja, Anderlik Tanja, Remde Hanna, Landwehr Laura-Sophie, Kimpel Otilia, Reuter Miriam, Schreiner Jochen, Wedekink Florian, Scherf-Clavel Oliver, Hoster Eva, Wollert Kai C, Budde Ilka, Altieri Barbara, Schwarzlmueller Paul, Reincke Martin, Wischhusen Jörg, Fassnacht Martin, Kroiss Matthias
LMU University Hospital, Department of Medicine IV, Ludwig-Maximilians-University, 80336 Munich, Germany.
Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, 97080 Wuerzburg, Germany.
Eur J Endocrinol. 2025 Jun 30;193(1):146-155. doi: 10.1093/ejendo/lvaf135.
PURPOSE: Treatment options for adrenocortical carcinoma (ACC), where mitotane remains a mainstay of therapy, are unsatisfactory. Response rates of ACC to immune checkpoint inhibition (ICI) are disappointing, and immune cells are scarce in ACC. Growth/differentiation factor 15 (GDF-15) is a cytokine impairing tumoural immune infiltration. We here aimed to assess the value of serum GDF-15 for the prognosis of ACC and as a predictor of response to ICI. METHODS: GDF-15 was measured in serum samples of 151 patients and correlated with clinical data. Serum GDF-15 was analysed in a second cohort of 46 ACC patients who received ICI, including 14 responders. mRNA expression of GDF15 and genes related to immune response was quantified in 58 ACC tumour samples. RESULTS: We found GDF-15 induction in ACC cells and patients upon mitotane treatment. In ACC patients, serum GDF-15 concentration below the median was associated with significantly longer patient survival. GDF-15 levels in responders to ICI were significantly lower than in non-responders (P = .0379), and patients with low GDF-15 levels had a significant longer progression-free survival than patients with higher GDF-15 serum levels (P = .036). Expression of pro-inflammatory immune-related genes was lower in ACC tissue with GDF-15 expression above the median. CONCLUSIONS: Mitotane increases GDF-15 levels and is associated with poor response to ICI. GDF-15 may mediate reduced infiltration with immune cells in ACC.
目的：米托坦仍是肾上腺皮质癌（ACC）主要治疗手段，但ACC的治疗方案并不理想。ACC对免疫检查点抑制（ICI）的反应率令人失望，且ACC中免疫细胞稀少。生长/分化因子15（GDF-15）是一种会损害肿瘤免疫浸润的细胞因子。我们旨在评估血清GDF-15对ACC预后的价值以及作为ICI反应预测指标的价值。 方法：检测了151例患者血清样本中的GDF-15，并将其与临床数据相关联。在另一组46例接受ICI治疗的ACC患者中分析了血清GDF-15，其中包括14例有反应者。对58例ACC肿瘤样本中GDF15及与免疫反应相关基因的mRNA表达进行了定量分析。 结果：我们发现米托坦治疗后ACC细胞和患者体内GDF-15被诱导。在ACC患者中，血清GDF-15浓度低于中位数与患者生存期显著延长相关。ICI反应者的GDF-15水平显著低于无反应者（P = 0.0379），且GDF-15水平低的患者无进展生存期显著长于GDF-15血清水平高的患者（P = 0.036）。GDF-15表达高于中位数的ACC组织中促炎免疫相关基因的表达较低。 结论：米托坦会增加GDF-15水平，并与ICI反应不佳相关。GDF-15可能介导了ACC中免疫细胞浸润的减少。
Cochrane Database Syst Rev. 2018-2-6
Endokrynol Pol. 2025
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