Elevated glucocorticoid (GC) activity may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. Adrenocortical carcinoma (ACC) provides a unique test case to assess correlates of GC activity, as approximately half of ACC patients exhibit excess GC production (GC+). ACC multi-omics were analyzed to identify molecular consequences of GC+ and assess the rationale for combining the glucocorticoid receptor (GR) antagonist relacorilant with an ICI. GC status, mRNA expression, and DNA mutation and methylation data from 71 adrenal tumors were accessed via The Cancer Genome Atlas. Expression of 858 genes differed significantly between GC- and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of three pathways involved in steroid synthesis and secretion in GC+ cases. Fifteen pathways, most related to NK cells and other immune activity, showed lower expression. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P = 0.003), CD8+ memory (P < 0.001), and NKT-cells (P = 0.014) were depleted in GC+ cases; tumor-associated neutrophils were enriched (P < 0.001). Given the pronounced differences between GC+ and GC- ACC, the effects of cortisol on NK cells were assessed in vitro (NK cells from human PBMCs stimulated with IL-2 or IL-12/15). Cortisol suppressed, and relacorilant restored, NK cell activation, proliferation, and direct tumor cell killing. Thus, GR antagonism may increase the abundance and function of NK and other immune cells in the tumor microenvironment, promoting immune response in GC+ ACC and other malignancies with GC+. This hypothesis will be tested in a phase 1 trial of relacorilant + ICI.

中文翻译：

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肾上腺肿瘤有助于深入了解皮质醇在 NK 细胞活性中的作用。

糖皮质激素 (GC) 活性升高可能会限制肿瘤免疫反应和免疫检查点抑制剂 (ICI) 的功效。肾上腺皮质癌 (ACC) 提供了一个独特的测试案例来评估 GC 活性的相关性，因为大约一半的 ACC 患者表现出过多的 GC 产生 (GC+)。分析 ACC 多组学以确定 GC+ 的分子后果并评估将糖皮质激素受体 (GR) 拮抗剂 relacorilant 与 ICI 组合的基本原理。通过癌症基因组图谱获取了来自 71 个肾上腺肿瘤的 GC 状态、mRNA 表达以及 DNA 突变和甲基化数据。858 个基因的表达在 GC- 和 GC+ ACC 病例之间存在显着差异。KEGG 通路分析显示，在 GC+ 病例中，参与类固醇合成和分泌的三个通路的基因表达较高。十五条路，大部分与NK细胞等免疫活性有关，呈较低表达。低甲基化主要在类固醇合成途径中观察到。在 GC+ 病例中，肿瘤浸润性 CD4+ 记忆 (P = 0.003)、CD8+ 记忆 (P < 0.001) 和 NKT 细胞 (P = 0.014) 被耗尽；肿瘤相关中性粒细胞富集（P < 0.001）。鉴于 GC+ 和 GC-ACC 之间的显着差异，在体外评估了皮质醇对 NK 细胞的影响（来自用 IL-2 或 IL-12/15 刺激的人 PBMC 的 NK 细胞）。皮质醇抑制和 relacorilant 恢复，NK 细胞活化、增殖和直接肿瘤细胞杀伤。因此，GR 拮抗作用可能会增加肿瘤微环境中 NK 和其他免疫细胞的丰度和功能，促进 GC+ ACC 和其他具有 GC+ 的恶性肿瘤的免疫反应。