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

Chung, Charlie, Yueh, Brian, Subhash, Santhilal, Eskiocak, Onur, Nizam, Aaron, Viola, Marissa, Belleau, Pascal, Kredentser, Ariel, Kapedani, Arisa, Krasnitz, Alexander, Simon, Ken, Meier, Werner, Frimer, Marina, Goldberg, Gary L, Beyaz, Semir (February 2026) Ancestrally diverse autologous patient-derived organoid - immune cell co-culture platform for addressing immunotherapeutic outcome disparities in high-grade endometrial cancer. Cancer Research Communications. ISSN 2767-9764

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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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > endometrial cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Chung, Charlie Yueh, Brian Subhash, Santhilal Eskiocak, Onur Belleau, Pascal Krasnitz, Alexander Beyaz, Semir
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Beyaz lab CSHL labs > Krasnitz lab CSHL Post Doctoral Fellows
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	19 February 2026
Date Deposited:	25 Mar 2026 13:50
Last Modified:	25 Mar 2026 13:50
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42120

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