Aaron Nizam

Clinical Implications of Genomic Loss of Heterozygosity in Endometrial Carcinoma

PURPOSE Homologous recombination deficiency, identified by homologous recombination deficiency gene alterations or high percentage of genome-wide loss of heterozygosity (gLOH), is associated with improved prognosis, platinum sensitivity (PS), and poly (ADP-ribose) polymerase inhibitor response in high-grade ovarian cancer. Since the copy number–high (CN-H) endometrial cancer molecular subtype (EC-MS) shares molecular features with high-grade ovarian cancer, our aim was to assign EC-MS on the basis of comprehensive genomic profiling (CGP) results and evaluate the gLOH status with clinical behavior of EC. METHODS Eighty-two epithelial EC tumor tissues were sequenced by hybrid capture–based CGP, and results were used to assign EC-MS (ultramutated, microsatellite instability–high, CN-low; CN-high). Retrospective chart review established clinical characteristics, including PS. Relationships of PS, EC-MS, gene alterations, and gLOH were assessed statistically. RESULTS PS and EC-MS of CN-H showed statistically significant difference in overall survival (OS). Most notably, when the CN-H EC-MS was subcategorized by gLOH status, there was a significant difference in OS with gLOH-H being associated with longer survival. Cox semi-proportional hazard modeling showed that gLOH, stage, and race were significant in modeling OS. CONCLUSION The method of assigning EC-MS by CGP demonstrates similar clinical features to previous reports of EC-MS assigned by other methods. CGP can also assess gLOH status with gLOH-H most commonly seen in CN-H tumors. CN-H, gLOH-H patients showed significantly improved OS (hazard ratio, 0.100 [0.02-0.51 95% CI]). Thus, gLOH status may be a meaningful prognostic biomarker within the CN-H tumors and possibly across EC-MS.

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

Abstract 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.