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

Integrative computational immunogenomic profiling of cortisol-secreting adrenocortical carcinoma

Affiliations

Integrative computational immunogenomic profiling of cortisol-secreting adrenocortical carcinoma

Jordan J Baechle et al. J Cell Mol Med. 2021 Nov.

Abstract

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.

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Conflict of interest statement

None.

Figures

FIGURE 1
FIGURE 1
Differentially expressed immune genes (DEIGs) of adrenocortical carcinoma stratified by cortisol secretion. (A) Categorization of all differentially expressed genes (DEGs). (B) Subcategorization of DEGs directly involved in immunological processes (DEIGs). (C) Heat map of DEIGs between CS‐ACC and nonCS‐ACC. (D) Heat map of mRNA expression relationships between DEIGs
FIGURE 2
FIGURE 2
Tumour‐infiltrating immune cell (TIIC) profiles of adrenocortical carcinoma (ACC). (A) Scaled absolute value of tumour infiltration by immune cell types estimated by CIBERSORTx in ACC tumours and stratified into subgroups by cortisol secretion, abs, absolute arbitrary units; ns = p‐value ≥ 0.05; *p‐value < 0.05. (B) Impact of differentially expressed TIIC subtypes (CD8 T cells, activated natural killer cells, M1 macrophages, activated dendritic cells) on overall (OS) and disease‐free survival (DFS). Regression analysis, expressed as univariate Cox regression hazard ratio (HR) and 95% confidence interval (95% CI): HR [lower 95% CI – higher 95% CI], bold = p‐value < 0.05
FIGURE 3
FIGURE 3
Steroid metabolism gene expression comparison by cortisol secretion and correlations to tumour‐infiltrating immune cells (TIICs). (A) Schematic of steroid metabolism enzyme and transcription factor gene expression. (B) Comparison of steroid metabolism gene expression by cortisol hypersecretion. (C) Heat map of steroid metabolism gene expression correlations with tumour‐infiltrating immune cell (TIIC) subtypes in nonCS‐ACC and CS‐ACC; ns = p‐value ≥ 0.05; *p‐value < 0.05, **p‐value < 0.01, ***p‐value < 0.001, ****p‐value < 0.0001
FIGURE 4
FIGURE 4
Differentially expressed immune genes (DEIGs) by cortisol secretion and associated patient outcomes in adrenocortical carcinoma (ACC). (A) The distribution of normalized mRNA expression of differentially expressed immune genes (DEIGs) in CS‐ACC and nonCS‐ACC tumours. (B) Overall survival (OS) univariate cox‐regression analysis according to gene mRNA expression. Regression analysis expressed as univariate Cox regression hazard ratio (HR) and 95% confidence interval (95% CI): HR [lower 95% CI – higher 95% CI]. (C) Disease‐free survival (DFS) univariate Cox regression analysis according to gene mRNA expression. Regression analysis, expressed as univariate Cox regression hazard ratio (HR) and 95% confidence interval (95% CI): HR [lower 95% CI – higher 95% CI]
FIGURE 5
FIGURE 5
Expression correlations between prognostic differentially expressed immune genes (DEIGs) and steroid metabolism genes. (A) Heat map of prognostic differentially expressed immune genes (DEIGs) and steroid metabolism genes in all ACC patients. (B) Heat map of prognostic DEIGs and steroid metabolism genes in all nonCS‐ACC patients. (C) Heat map of prognostic DEIGs and steroid metabolism genes in CS‐ACC patients
FIGURE 6
FIGURE 6
Immunosuppressive signature of cortisol‐secreting adrenocortical carcinoma (CS‐ACC). (A) Heat map of immunosuppressive signature of CS‐ACC with multiple intercorrelated gene mRNA expression sub‐clusters. (B) Heat map of individual gene expression contributing to CS‐ACC immunosuppressive signature and correlations with tumour‐infiltrating immune cell (TIIC) subtypes. (C) Overall survival (OS) comparing low and high expression of the total signature of ACC tumours. (D) Disease‐free survival (DFS) comparing low and high expression of the total signature of ACC tumours

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