Ancestrally diverse autologous patient-derived organoid – immune cell co-culture platform for addressing immunotherapeutic outcome disparities in high-grade endometrial cancer

Abstract High-grade endometrial cancers (HGECs) disproportionately affect women of African ancestry and often resist currently available immunotherapies. Defining the mechanisms driving this resistance is impeded by a lack of preclinical models that preserve ancestral diversity and patient-matched tumor-immune interactions without confounding alloreactivity. To address this gap, we established a biobank of 85 endometrial cancer patient-derived organoids (PDOs) from a diverse cohort, enriched for HGEC PDOs from African American patients, and paired these with autologous immune cells to develop a patient-specific PDO-immune cell co-culture platform with real-time live-imaging readouts. Using this system, we found that HGECs evade immune surveillance through pronounced suppression of major histocompatibility complex (MHC) class I and II antigen presentation pathways relative to matched normal counterparts. Restoring antigen presentation, either by IFNγ stimulation or epigenetic reprogramming via Enhancer of Zeste Homologue 2 (EZH2) inhibition, rescued MHC expression and sensitized HGEC PDOs to autologous T cell-mediated cytotoxicity. Extending the platform to NK cells revealed heightened killing of low-MHC-I PDOs. Consistent with clinical observations, mismatch repair-deficient HGEC PDOs exhibited stronger immune engagement than mismatch repair-proficient counterparts. Finally, this platform enabled evaluation of the safety and efficacy of emerging immunotherapies, including protease-activatable bispecific T-cell engagers (TCEs) and EGFR-targeted chimeric antigen receptor (CAR) T cells. Together, this sustainable, scalable, ancestrally diverse autologous PDO-immune cell co-culture platform offers a robust resource for dissecting immune evasion mechanisms and accelerating the development of new immunotherapies to address disparities in endometrial cancer outcomes.