Multiplatform Computational Analysis of Mast Cells in Adrenocortical Carcinoma Tumor Microenvironment

Abstract

Introduction: Immunotherapeutic response failure of adrenocortical carcinomas (ACC) highlights a need for novel strategies. Recent studies have alluded to tumor mast cell (MC) infiltration and improved patient outcomes. In this study, we examine MC activity within the ACC microenvironment to offer new insights for novel therapeutic targets. Methods: CIBERSORTx immunogenomic deconvolution of ACC tumors (TCGA, N=79). estimated tumor immune infiltrating MCs. We evaluated MC signaling genes for their prognostic potential characterizing pro- and anti-tumor signatures and impact on overall (OS) and disease-free(DFS) survival in ACC. Results: MC infiltration was strongly associated with favorable DFS in ACC patients. Anti-tumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and pro-tumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) expression signatures were compiled from genes with significantly prolonged and shortened prognosis (OS, DFS p<0.05). Anti-tumor MC signature emerged as the predominant phenotype associated with improved OS and DFS and notably downregulated in immunotherapy resistant cortisol-secreting ACC (CS-ACC). Conclusion: Increased mast cell infiltration in ACC microenvironment correlates with a favorable prognosis. Mast cells play complex mixed anti- and pro-tumor roles in ACC, with predominantly anti-tumor activity. Modulating tumor mast cell infiltration and activity may offer a potential target for novel synergistic immunotherapies for the treatment of CS-ACC.