Ancestrally Diverse Autologous Patient-Derived Organoid-Immune Cell Coculture Platform for Addressing Immunotherapeutic Outcome Disparities in High-Grade Endometrial Cancer.

High-grade endometrial cancers (HGEC) 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 (PDO) 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 coculture 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 their matched normal counterparts. Restoring antigen presentation, either by IFNγ stimulation or epigenetic reprogramming via enhancer of zeste homolog 2 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 (MMR)-deficient HGEC PDOs exhibited stronger immune engagement than their MMR-proficient counterparts. Finally, this platform enabled evaluation of the safety and efficacy of emerging immunotherapies, including protease-activatable bispecific T-cell engagers and EGFR-targeted chimeric antigen receptor T cells. Together, this sustainable, scalable, ancestrally diverse autologous PDO-immune cell coculture platform offers a robust resource for dissecting immune evasion mechanisms and accelerating the development of new immunotherapies to address disparities in endometrial cancer outcomes. SIGNIFICANCE: The efficacy of immunotherapy for HGECs remains limited, partly because current preclinical models poorly capture tumor heterogeneity and patient-specific immune microenvironment. These cancers disproportionately affect women of African ancestry, yet most studies rely on European ancestry samples. We developed an autologous PDO and immune cell coculture platform from patients of diverse ancestries. This system enables patient-level analysis of tumor-immune interactions to support development and testing of novel immunotherapeutic strategies.