Multiplexed imaging mass cytometry reveals tumor-immune microenvironment-dependent hormone receptor expression in adult type ovarian granulosa cell tumors

Abstract Adult-type granulosa cell tumors (AGCTs) are rare ovarian tumors with few effective treatments for recurrent disease. To elucidate spatial features and cellular interactions within the AGCT tumor microenvironment (TME), we applied imaging mass cytometry (IMC) using a 34-marker panel on 130 regions from 24 AGCT samples, profiling over 900,000 single cells. Analysis confirmed the immune “cold” phenotype of AGCTs and showed higher macrophage abundance in recurrent compared to 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 TME composition, we defined two AGCT subtypes: AGCT-1 and AGCT-2 with distinct FOXL2+ cell distributions, differences in progesterone receptor (PR) expression, and unique transcriptomic profiles. Our findings highlight the role of macrophages, Foxl2+ subpopulations, and extracellular matrix (ECM) in AGCT progression and suggest AGCT subtype-specific vulnerabilities that could inform personalized therapies for this rare malignancy.