Multiplexed Imaging Mass Cytometry Reveals Tumor-immune Microenvironment-dependent Hormone Receptor Expression in Adult-Type Ovarian Granulosa Cell Tumors.

UNLABELLED: Adult-type granulosa cell tumors (AGCT) are rare ovarian tumors with few effective treatments for recurrent disease. To elucidate spatial features and cellular interactions within the AGCT tumor microenvironment, we applied imaging mass cytometry using a 34-marker panel on 130 regions from 24 AGCT samples, profiling more than 900,000 single cells. Analysis confirmed the immune "cold" phenotype of AGCTs and showed higher macrophage abundance in recurrent compared with primary tumors. We observed substantial heterogeneity in tissue architecture across samples, including variable presence of FOXL2+ cells embedded in collagen-rich regions (FOXL2+COL1A1+ cells). Based on tumor microenvironment composition, we defined two AGCT subtypes: AGCT-1 and AGCT-2 with distinct FOXL2+ cell distributions, differences in progesterone receptor expression, and unique transcriptomic profiles. Our findings highlight the role of macrophages, Foxl2+ subpopulations, and the extracellular matrix in AGCT progression and suggest AGCT subtype-specific vulnerabilities that could inform personalized therapies for this rare malignancy.

SIGNIFICANCE: We discovered two histologically and molecularly distinct forms of AGCTs that differ in cell composition, immune activity, and hormone signals. These findings point to new opportunities for more personalized treatment of this rare ovarian cancer.