Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma.

摘要: Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventional chemotherapeutics agents. Early diagnosis, followed by radical surgical resection plus/minus adjuvant mitotane therapy, nowadays the only valuable option. Unfortunately, one out of four patients has metastatic disease at diagnosis and most radically resected ACC are destined recur with local or disease. Numerous efforts aimed identifying molecular alterations crucial for pathogenesis have been extensively conducted, hope develop new treatments. Indeed, multiple genes pathways identified as potentially targetable in patients; however, despite strong preclinical rationale, translational findings clinical trials led date disappointing results. The immunotherapeutic intervention targeting T-cell checkpoint molecules proposed well, but results obtained early studies indicate that would be unlikely benefit from immunotherapy. Genetic different involved carcinogenesis also known substrates resistance Among them, β-catenin gene CTNNB1 TP53 frequently mutated samples. Overactivation pathway loss p53 protein function potential tumor-intrinsic factors that, impacting on ability cells recruit dendritic cells, leading exclusion, put this tumor among those resistant Moreover, steroid phenotype, which implies glucocorticoids hypersecretion subset ACC, contributes generating an immunosuppressive microenvironment. Here, we review immunotherapy highlight mechanisms driving failure suggesting possible approaches overcome resistance.