米托坦治疗肾上腺皮质癌可诱导肿瘤分泌生长分化因子15：对预后不良及免疫治疗反应受损的影响。

Mitotane treatment of adrenocortical carcinoma induces tumoural secretion of GDF-15: impact on poor prognosis and impaired responsiveness to immunotherapy.

作者信息

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

机构信息

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.

出版信息

Eur J Endocrinol. 2025 Jun 30;193(1):146-155. doi: 10.1093/ejendo/lvaf135.

DOI:10.1093/ejendo/lvaf135

PMID:40570159

Abstract

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.

摘要

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。