Autocrine signaling in hormonally active cancer induces antigen expression for immunotherapy

Endocrine, but also many non-endocrine cancers produce hormones that modulate immune-recognition and -therapy. We used adrenocortical carcinoma (ACC) as model that produces high amounts of glucocorticoids (GCs) and studied cancer antigen expression and recognition. Our study revealed that the oncofetal antigen ROR1 is induced by autocrine GC-signaling and that its transcription is regulated by GC-activated human glucocorticoid receptor (hGR) in complex with STAT3. To exploit the exalted ROR1 expression on ACC, we engineered ROR1-specific chimeric antigen receptor (CAR)-T cells that were shieled from the immune-suppressive effect of GCs, and conferred complete remission of GC-producing ACC xenografts in vivo . Our study identifies autocrine signaling as a mechanism that induces antigen expression in hormonally active cancer, which can be leveraged for effective immunotherapy with genetically-engineered CAR-T cells. One-Sentence Summary Autocrine glucocorticoid (GC) signaling induces the oncogenic driver ROR1 in hormonally active adrenocortical carcinoma (ACC), and exposes ACC to elimination by GC-resistant ROR1-specific CAR-T cells.