J. J. Baechle1, D. N. Hanna2, J. C. Rathmell4, K. W. Rathmell5, N. Baregamian3 1Meharry Medical College,School Of Medicine,Nashville, TN, USA 2Vanderbilt University Medical Center,Department Of Surgery,Nashville, TN, USA 3Vanderbilt University Medical Center,Division Of Surgical Oncology & Endocrine Surgery,Nashville, TN, USA 4Vanderbilt University Medical Center,Department Of Pathology, Microbiology And Immunology,Nashville, TN, USA 5Vanderbilt University Medical Center,Division Of Hematology And Oncology,Nashville, TN, USA
Introduction: Nearly 50% of highly aggressive, but rare adrenocortical carcinomas (ACC) are hormone-producing. Recent immunotherapy clinical trials showed significant immunoresistance in cortisol-secreting ACC (CS-ACC). We aim to characterize this immunosuppressive signature within the tumor-infiltrating immune cell (TIIC) landscape of CS-ACC to decipher immunoresistance using comprehensive multiplatform computational immunogenomic analytic approaches.
Methods: The gene expression profiles of ACC tumors were analyzed and stratified by cortisol hypersecretion (N=33 CS-ACC) using The Cancer Genome Atlas (TCGA) ACC tumor cohort (N=92). To estimate the TIIC subtypes for immunogenomic pattern analysis, TCGA genomic sequencing data was further deconvoluted with CIBERSORTx computational analytic platform. The Panther Classification System availed generation and selection of significant gene profiles related to immunological processes in ACC. The ACC gene interactions and clustering were assessed with Cytoscape platform. R programing was used to assess the prognostic value of each gene’s mRNA expression and DNA methylation. Survival analysis was performed using Cox regression models.
Results: Multiplatform deconstructing analytical assessment of ACC tumors reconstructed a complex immunosuppressive TME in CS-ACC with notably significant depletion of Tγδ cells, and increased infiltration of activated dendritic cells (DCa), resting mast cell and neutrophils. Of the 1,021 genes with significantly altered mRNA expression in CS-ACC, 45 (4%) were directly related to immunological processes, of which 44 showed decreased and 1 (CCRL2) showed increased mRNA expression levels in ACC tumor microenvironment (TME). Of these 45 gene hits, the mRNA expression of 19 (42%) were significant prognostic indicators with positive associations for both overall survival (OS) and disease-free survival (DFS) in CS-ACC. The DNA methylation of 5 genes associated with significant risk factors and negative associations for OS and DFS had identified GBP2, HLA-F, Jak3, SIRPA, TLR5 genes with altered primary prognostic expression signature in CS-ACC tumors. Significant increase in mRNA expression levels of immunosuppressive CCRL2 and decreased DNA methylation were also observed in CS-ACC tumors. The CCRL2 overexpression was also negatively associated with DFS.
Conclusion: Comprehensive multiplatform immunogenomic computational analyses of ACC tumors unveiled a complex immunosuppressive expression profile with direct impact on survival and poor prognosis in patients with CS-ACC. We identified several primary immunogenomic prognostic indicators and targets within tumor immune landscape of CS-ACC. These important findings will potentiate future studies focusing on identifying novel immunotherapeutic strategies to overcome the immunotherapeutic resistance in patients with CS-ACC tumors.