Adrenocortical Carcinoma Steroid Profiles: In Silico Pan-Cancer Analysis of TCGA Data Uncovers Immunotherapy Targets for Potential Improved Outcomes
Autor: | João C. D. Muzzi, Jessica M. Magno, Milena A. Cardoso, Juliana de Moura, Mauro A. A. Castro, Bonald C. Figueiredo |
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Rok vydání: | 2021 |
Předmět: |
Adult
Male 0301 basic medicine steroidogenesis Adolescent Endocrinology Diabetes and Metabolism In silico medicine.medical_treatment Druggability PD-1/PD-L1/PD-L2 Diseases of the endocrine glands. Clinical endocrinology Transcriptome Young Adult 03 medical and health sciences Endocrinology 0302 clinical medicine Immune system Databases Genetic Adrenocortical Carcinoma Tumor Microenvironment Adjuvant therapy Humans Medicine Adrenocortical carcinoma Computer Simulation CD276 Immune Checkpoint Inhibitors Original Research Aged Cell Proliferation business.industry fungi Cancer Immunotherapy CD8+ T lymphocytes Middle Aged RC648-665 medicine.disease Adrenal Cortex Neoplasms Survival Rate 030104 developmental biology PDCD1/CD274/PDCD1LG2 B7-H3 030220 oncology & carcinogenesis Cancer research Female business |
Zdroj: | Frontiers in Endocrinology Frontiers in Endocrinology, Vol 12 (2021) |
ISSN: | 1664-2392 |
Popis: | 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. |
Databáze: | OpenAIRE |
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