Endocrine Abstracts

Introduction: Excess glucocorticoid (GC) activity has been implicated in the pathophysiology of multiple cancer types. For instance, approximately half of adrenocortical carcinoma (ACC) patients exhibit excess GC (GC+). This provides a unique opportunity to study correlates of GC activity, such as a possible suppression of tumor immune response and immune checkpoint inhibitor (ICI) efficacy due to the broad immunosuppressive effects of GC. ACC multi-omics data can be used to identify the molecular consequences of GC activity and assess the rationale for combining relacorilant, a selective glucocorticoid receptor (GR) modulator, 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: A significant difference in the expression of 858 genes was observed between GC- and GC+ ACC cases. In the GC+ cases, KEGG pathway analysis showed higher gene expression of 7 pathways involved in steroid synthesis and secretion, as well as lower expression in 19 pathways, 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, while tumor-associated neutrophils were enriched (P<.001). Moreover, 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: By reducing the abundance of immune cells and immune-related transcripts in GC+ ACC, GC may limit response to ICI therapy. Selective GR modulators such as relacorilant may be able to 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.