Adrenocortical carcinoma is a rare endocrine cancer of the adrenal gland, with an incidence of approximately one case per million people per year. Despite this rarity, it is notable for its high aggressiveness and marked heterogeneity between patients, with a five-year survival rate ranging from 16 to 44%. Complete surgical resection of localized tumors is the only curative option, but the risk of recurrence remains high (30 to 75%), while unresectable or metastatic forms are managed essentially with palliative treatments. A recently described subtype, characterized by a CpG island methylator phenotype (CIMP), has been associated with a particularly poor prognosis, although neither the causes of this phenotype nor its functional link with clinical outcome had been elucidated.
To address these questions, the team combined several approaches using patient cohorts (notably data from the European ENSAT network and the TCGA atlas) and cellular models. Methylation levels were measured by reduced representation bisulfite sequencing (RRBS), gene expression by RNA-seq, and lymphocytic infiltration assessed by immunohistochemistry targeting the CD3 marker in tumors with high and low CIMP. The effect of a demethylating agent, 5-azacytidine, was also tested on adrenocortical tumor cell lines (H295R, MUC1) as well as on a non-tumoral endothelial cell line.
This work establishes that the CIMP phenotype is linked to overexpression of the DNA methyltransferases DNMT1 and DNMT3A, itself driven by a gain in copy number of the corresponding genes and by cellular hyperproliferation. Importantly, the authors demonstrate that hypermethylation contributes to tumor aggressiveness by promoting immune escape: high-CIMP tumors display a lower abundance of infiltrating immune cells, with promoter methylation repressing genes involved in the immune response. Treatment with 5-azacytidine proved capable of reducing promoter methylation while reactivating the expression of these genes, thereby at least partially reversing the observed phenotype.
These results delineate a mechanism linking cell proliferation, increased methyltransferase activity, and the establishment of the CIMP phenotype, which in turn is responsible for a tumor microenvironment depleted of immune cells. The authors suggest that co-administration of demethylating agents could enhance the efficacy of immunotherapy and represent a new therapeutic approach for patients with high-CIMP adrenocortical carcinoma.