Introduction: Elevated glucocorticoid (GC) activity, while difficult to accurately quantify, has been implicated in the pathophysiology of multiple cancer types. Approximately half of adrenocortical carcinoma (ACC) patients exhibit excess GC (GC+), which provides a unique test case to assess correlates of GC activity. The broad immunosuppressive effects of GC may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. ACC multi-omics were analyzed to identify the molecular consequences of GC activity and assess the rationale for combining relacorilant, a glucocorticoid receptor (GR) antagonist, with an ICI in GC+ ACC.
Methods: GC status, mRNA expression, DNA mutation, and DNA methylation data from distinct adrenal resections (n=71) were accessed via The Cancer Genome Atlas (TCGA). To deconvolute immune cell type abundance, xCell was applied to the mRNA data. Random forest was used to derive gene signatures.
Results: The expression of 858 genes differed significantly between GC- and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of 7 pathways involved in steroid synthesis and secretion in GC+ cases. Nineteen pathways showed lower expression, most of which were related to natural killer cells, T-cells, and immune activity. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P=.003), CD8+ memory (P<.001), and NKT-cells (P=.014) were depleted in GC+ cases, while tumor-associated neutrophils were enriched (P<.001). Higher tumor mutation burden (TMB) was observed in the GC+ cases (P=.029). A gene signature predictive of GC status in ACC was derived and applied to other cancer types to identify tumors with GC+-like transcriptional profiles.
Conclusions: Reduced abundance of immune cells and immune-related transcripts in GC+ ACC provides insight into the mechanisms by which GC may limit response to ICI therapy. GR antagonism may increase immune related transcripts, thus promoting tumor immune response in GC+ ACC and other malignancies with elevated GC activity. This hypothesis will be tested in a Phase 1 trial of relacorilant + ICI.
Citation Format: Andrew E. Greenstein, Mouhammed Amir Habra, Marzena Mura, Paweł Biernat, Marek J. Piatek, Andreas Grauer, Stacie Peacock Shepherd. Suppression of tumor immune activity in adrenocortical carcinoma with excess glucocorticoid [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-130.