Adrenocortical Carcinoma Steroid Profiles: In Silico Pan-Cancer Analysis of TCGA Data Uncovers Immunotherapy Targets for Potential Improved Outcomes

Abstract

Despite progress in understanding the biology of adrenocortical carcinoma (ACC), treatment options have not dramatically changed in the last three decades, nor have we learned how to avoid some of its long-term side effects. Our goal was to improve the understanding of immune pathways that may include druggable targets to enhance immune responses of patients with ACC, focusing on immune evasion and the activation of immune cells against ACC. Our strategy was aimed at improving insight regarding gene expression without steroid interference. Using approaches based on high and low steroid phenotypes (HSP and LSP, respectively), we characterized immune pathways using The Cancer Genome Atlas (TCGA) ACC cohort data. Although previous studies have suggested that patients with ACC receive minimal benefit from immunotherapy, high expression of immune modulators was noted in patients with LSP, suggesting the activation of these biomarkers may be an important adjuvant therapy target after clearance of excess glucocorticoids. In addition, patients with LSP ACC had higher immune cell infiltration than patients with HSP ACC and other cancer subtypes. Our findings can be summarized as follows (1): we confirmed and improved the definition of two immune response pathways to ACC (HSP and LSP) based on in silico transcriptome analysis (2), we demonstrated the steroid profile should be considered, otherwise analyses of ACC immune characteristics can generate confounding results (3), among the overexpressed immunotherapy targets, we demonstrated that LSP was rich in PDCD1LG2 (PD-L2) and both HSP and LSP overexpressed CD276 (B7-H3), which was associated with resistance to anti-PD1 therapy and may have accounted for the modest results of previous clinical trials, and (4) identification of patients with LSP or HSP ACC can be used to help determine whether immunotherapy should be used. In conclusion, we highlighted the differences between LSP and HSP, drawing attention to potential therapeutic targets (CD276, PDCD1, and PDCD1LG2). Treatments to reduce immune evasion, as well as the use of other natural and pharmacological immune activators, should include prior pharmacological inhibition of steroidogenesis. Attempts to combine these with tumor cell proliferation inhibitors, if they do not affect cells of the immune system, may produce interesting results.

Expression of glucocorticoid receptor (GR) and clinical significance in adrenocortical carcinoma

“…The interplay between cortisol production and the immune status in ACC has been a topic of recent studies (17,31). One study based on TCGA dataset analysis found that ACC patients with low steroid phenotype had higher expression of immune checkpoints gene and immune cell infiltration than patients with high steroid phenotype (17).…”

“…The interplay between cortisol production and the immune status in ACC has been a topic of recent studies (17,31). One study based on TCGA dataset analysis found that ACC patients with low steroid phenotype had higher expression of immune checkpoints gene and immune cell infiltration than patients with high steroid phenotype (17). Moreover, Landwehr and colleagues performed immunofluorescence analysis to visualize tumorinfiltrating T cells in 146 ACC tissue, and demonstrated that glucocorticoid excess is associated with T cell depletion and unfavorable prognosis in ACC (31).…”

“…It is well known that glucocorticoids can suppress immunity and promote tumor development by regulating the level of tumor-infiltrating immune cells. Recently, Figueiredo and colleagues conducted a comprehensive silico transcriptome analysis of ACC based on public databases, and found that immune signature was associated with the steroid profiles of ACC, patients with low steroid phenotype had a higher pattern of immune activators and higher immune cell infiltration than patients with high steroid phenotype (17). This study highlighted the impact of excess steroids on the immune system interaction with ACC tumors, drawing attention to potential therapeutic targets.…”

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

“…Although in an international, multicenter phase Ib trial (NCT01772004), avelumab administered to 50 ACC patients previously treated with mitotane or platinum-based chemotherapy showed only a modest clinical activity (a partial response in 6% of patients, stable disease in 42%, and disease progression in 46% of patients [ 68 ]) some prolonged OS is observed in several studies [ 69 ] suggesting a benefit in a subset of patients. Besides endogenous steroid hypersecretion in functioning ACCs, glucocorticoids are also frequently prescribed as supplementation to treat adrenal deficiency in ACC patients treated with mitotane or following adrenal surgery and might interact with immunotherapies [ 70 ]. Combining the administration of immune checkpoint inhibitors with drugs targeting the Wnt-β catenin and TP53 pathways could be an attractive treatment paradigm for future studies [ 71 ].…”

Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis

“…Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine malignancy with a bimodal age distribution and distinct characteristics between pediatric and adult tumors [ 1 , 2 ]. ACC is characterized by a highly proliferative and immune-suppressed tumor microenvironment, high production of corticoids, TP53 mutation, and an upregulation of the WNT/β-Catenin pathway [ 3 , 4 , 5 , 6 ].…”