Mitotane treatment of adrenocortical carcinoma induces tumoural secretion of GDF-15: impact on poor prognosis and impaired responsiveness to immunotherapy.

Purpose: Treatment options for adrenocortical carcinoma (ACC), where mitotane remains a mainstay of therapy, are unsatisfactory. Response rates of ACC to immune checkpoint inhibition (ICI) are disappointing, and immune cells are scarce in ACC. Growth/differentiation factor 15 (GDF-15) is a cytokine impairing tumoural immune infiltration. We here aimed to assess the value of serum GDF-15 for the prognosis of ACC and as a predictor of response to ICI.

Methods: GDF-15 was measured in serum samples of 151 patients and correlated with clinical data. Serum GDF-15 was analysed in a second cohort of 46 ACC patients who received ICI, including 14 responders. mRNA expression of GDF15 and genes related to immune response was quantified in 58 ACC tumour samples.

Results: We found GDF-15 induction in ACC cells and patients upon mitotane treatment. In ACC patients, serum GDF-15 concentration below the median was associated with significantly longer patient survival. GDF-15 levels in responders to ICI were significantly lower than in non-responders (P = .0379), and patients with low GDF-15 levels had a significant longer progression-free survival than patients with higher GDF-15 serum levels (P = .036). Expression of pro-inflammatory immune-related genes was lower in ACC tissue with GDF-15 expression above the median.

Conclusions: Mitotane increases GDF-15 levels and is associated with poor response to ICI. GDF-15 may mediate reduced infiltration with immune cells in ACC.