Intratumor microbiota modulates adrenocortical cancer responsiveness to mitotane

The infiltrating microbiota represents a novel cellular component of solid tumor microenvironment that can influence tumour progression and response to therapy. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy for which mitotane (MTT) treatment represents the first line therapy, though its efficacy is limited to a therapeutic window level (14-20mg/L). Novel markers able to predict those patients who would benefit from MTT therapy are urgently needed to improve patient’s management. The aim of our study was to evaluate the presence of intratumoral bacterial microbiota DNA in 26 human ACC tissues versus 9 healthy adrenals; moreover, the association between the relative bacterial composition profile, the tumor mass characteristics and MTT ability to reach high circulating levels in the early phase of treatment, was explored. We found the presence of bacterial DNA in all adrenal samples from both tumours and healthy cortex specimens, documenting significant differences in the microbial composition between malignancy and normal adrenals: in detail, the ACC tissues were characterised by a higher abundance of the Proteobacteria phylum (especially the Pseudomonas and Serratia genera). In addition, the Proteobacteria low abundance was negatively associated with tumour size, Ki67 and cortisol-secretion. Mitotane levels reached higher levels at 9 months in ACC patients with high abundance of Proteobacteria, Pseudomonas and Serratia, and with low abundance of Bacteroidota, Firmicutes and Streptococcus. These findings are the first indication that human ACCs are characterised by infiltrating bacteria and their specific abundance profile seems to influence the increase in circulating MTT levels at 9 months.