Integrative computational immunogenomic profiling of cortisol-secreting adrenocortical carcinoma

J Cell Mol Med. 2021 Nov;25(21):10061-10072. doi: 10.1111/jcmm.16936. Epub 2021 Oct 19.


Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy. Nearly half of ACC tumours overproduce and secrete adrenal steroids. Excess cortisol secretion, in particular, has been associated with poor prognosis among ACC patients. Furthermore, recent immunotherapy clinical trials have demonstrated significant immunoresistance among cortisol-secreting ACC (CS-ACC) patients when compared to their non-cortisol-secreting (nonCS-ACC) counterparts. The immunosuppressive role of excess glucocorticoid therapies and hypersecretion is known; however, the impact of the cortisol hypersecretion on ACC tumour microenvironment (TME), immune expression profiles and immune cell responses remain largely undefined. In this study, we characterized the TME of ACC patients and compared the immunogenomic profiles of nonCS-ACC and CS-ACC tumours to assess the impact of differentially expressed genes (DEGs) by utilizing The Cancer Genome Atlas (TCGA) database. Immunogenomic comparison (CS- vs. nonCS-ACC tumour TMEs) demonstrated an immunosuppressive expression profile with a direct impact on patient survival. We identified several primary prognostic indicators and potential targets within ACC tumour immune landscape. Differentially expressed immune genes with prognostic significance provide additional insight into the understanding of potential contributory mechanisms underlying failure of initial immunotherapeutic trials and poor prognosis of patients with CS-ACC.

Keywords: adrenocortical carcinoma; cortisol secreting adrenocortical carcinoma; cushing's syndrome; immunometabolism; tumour immunology; tumour microenvironment.

MeSH terms

  • Adrenal Cortex Neoplasms / etiology*
  • Adrenal Cortex Neoplasms / metabolism*
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Carcinoma / etiology*
  • Adrenocortical Carcinoma / metabolism*
  • Adrenocortical Carcinoma / pathology
  • Computational Biology* / methods
  • Databases, Genetic
  • Disease Susceptibility
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hydrocortisone / metabolism*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism
  • Tumor-Associated Macrophages / pathology


  • Hydrocortisone