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.
Highlights
Adrenocortical carcinoma (ACC) is a rare highly aggressive malignancy of which >80% are steroidogenic [1,2,3,4]
The prognostic differences were remarkable, with only 3 death events (9.7%) in patients with low steroid phenotype (LSP) versus 24 (51.1%) in patients with high steroid phenotype (HSP). This was in addition to a higher proportion of advanced cancer stages observed in the HSP group, which may have been associated with a higher proliferation rate
We demonstrated the immune system capabilities were dramatically better in patients with LSP (Figures 1 and 2), which is in agreement with studies describing the immune suppression caused by excess glucocorticoids [12]
Summary
Adrenocortical carcinoma (ACC) is a rare highly aggressive malignancy of which >80% are steroidogenic [1,2,3,4]. The phenotypes seen with molecular changes in ACC may be largely derived from the dominant co-secretion of cortisol and androgens These differences in combinations of steroid underlie the importance of defining steroid phenotypes and identifying the relevant genetic alterations that characterize the various immune system profiles observed. De Reyniès et al [8] and Giordano et al [9] defined two ACC subgroups, C1A and C1B, while Zheng et al [5] clustered ACC mRNA-seq data in two subgroups with a high steroid phenotype (HSP) and low steroid phenotype (LSP), separating the expression pattern of genes in the steroid synthesis pathway. Zheng and colleagues found an immune signature associated with the LSP profile upon comparison of immune-suppressed ACC with strong steroidogenesis [5]
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