OR16-04 Androgen Deprivation Restricts Anti-tumor Immunity In Adrenocortical Carcinoma
Authors: Warde Kate M , Smith Lorenzo , Biochemistry B S , Stubben Chris J , Willet Parker W , Castaneda-Hernandez Guadalupe , Liu Lihua , Basham Kaitlin 
Published: October 2023

Abstract
Disclosure: K.M. Warde: None. L. Smith: None. C.J. Stubben: None. P.W. Willet: None. G. Castaneda-Hernandez: None. L. Liu: None. K. Basham: None.
Adrenocortical carcinoma (ACC) is a rare cancer that is often diagnosed late and progresses rapidly, resulting in routinely poor outcomes. Through The Cancer Genome Atlas (TCGA) and other genomic studies, homozygous loss of ZNRF3 was newly identified as a frequent genetic alteration in human ACC tumors. ZNRF3 is an E3 ubiquitin ligase that negatively regulates Wnt signaling by degrading Wnt receptors. To examine the role of ZNRF3 in adrenal biology, we generated a Znrf3 conditional knockout (cKO) mouse model. Despite roust early hyperplasia, we found that Znrf3 cKO mice only develop adrenal tumors with advanced aging. Moreover, tumors emerge in a sex dimorphic manner whereby males, who exhibit a high myeloid immune response, predominately get benign tumors and females, who have a dampened myeloid response, develop metastatic ACC. This phenomenon is reflected clinically in patients whereby the incidence of ACC is up to 2.5x higher in women compare to men. In human ACC patients, females exhibit a lower myeloid signature compared to males. Moreover, a low myeloid response signature is associated with shorter progression-free and overall survival. These data suggest a potential relationship between anti-tumor immunity and sex in ACC, yet the underlying mechanisms remain unclear. Sex differences are common in cancer, and although there are many potential factors, gonadal hormones including androgens and estrogens, have been implicated as major biological drivers. Previous studies of the adrenal cortex highlight a specific role for androgens in repressing stem cell recruitment and proliferation. We hypothesized androgens promote anti-tumor immunity to help protect against ACC. To test this hypothesis, we castrated male Znrf3 cKO mice to lower androgen levels. We found that androgen deprivation significantly reduced myeloid cell infiltration, resulting in significantly larger adrenals in castrated as compared to sham controls. RNA-seq analysis revealed a decrease in immune activation pathways and monocyte-derived myeloid cell populations. Additionally, pro-inflammatory cytokines, including TNF, INFG, and IL-6, were significantly inhibited in castrated animals compared to controls. These data support a protective role for androgens in ACC through driving an intra-adrenal myeloid immune response. Consistent with these results, analysis of the TCGA-ACC patient cohort demonstrated that high androgen receptor expression is associated with better overall survival. Taken together, our results reveal an important role for androgens in promoting anti-tumor immunity in a mouse model of ACC, and we highlight the prognostic value of androgen receptor expression in patients. Further understanding of androgen signaling and downstream biological mechanisms that regulate the immune response may ultimately offer novel therapeutics and improve patient outcomes in ACC.
Presentation: Friday, June 16, 2023