Abstract A019: Autologous patient-derived organoid-immune cell co-culture platform for therapeutics discovery in high-grade endometrial cancer

Abstract

Abstract Endometrial cancer is the most common gynecologic malignancy with increasing incidence and mortality rates. Recurrent endometrial cancers, which are mostly from high-grade endometrial cancers (HGEC), have limited treatment options and display extremely poor response rate upon chemotherapies, thus showing very poor prognosis. Immunotherapy revolutionized the field of cancer medicine, but lack of scalable and sustainable pre-clinical models for HGEC poses a significant challenge in studying critical immunological aspects of HGEC. We therefore established a comprehensive endometrial cancer biobank comprising primary tissues, patient-derived organoids (PDO), and their matching immune cells from all existing HGEC types, enabling us to establish an autologous interaction between cancer and immune cells in vitro. Inactivation of antigen processing and presentation (APP) pathways is one of the major mechanisms for immune evasion in many cancer types including HGEC. Using a subset of our biobank, we performed bulk RNA-seq on 11 normal-cancer PDO pairs and found that genes involved in APP pathways, MHC-II in particular, are downregulated in HGEC organoids. We found that dampened MHC expression can be reverted by external stimuli such as IFNγ and Tazemetostat. We then assessed the effects of enhanced MHC-I and -II expression mediated by the two molecules on cancer-immune cell interactions by setting up organoid-immune cell co-cultures using autologous PBMC, CD4, and CD8 T cells. Our results suggest that cell signaling and epigenetic manipulations on HGEC can be exploited to enhance immune cell-mediated apoptosis. Using our co-culture platform, we next evaluated the efficacy of different immunotherapeutic modalities such as NK cell transfer, bi-specific T-cell engagers, and CAR-T cells on HGEC. Our proof-of-principle experiments demonstrate the utility of our co-culture system in studying the autologous cancer-immune cell interactions from the same patient ex vivo. Our sustainable and scalable testing platform could be used to assess the safety and efficacy of current therapeutics or to identify new therapeutics that enhance immune responses against advanced cancers lacking effective treatment options such as HGEC. Citation Format: Charlie Chung, Aaron Nizam, Brian Yueh, Santhilal Subhash, Marina Frimer, Gary L. Goldberg, Semir Beyaz. Autologous patient-derived organoid-immune cell co-culture platform for therapeutics discovery in high-grade endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A019.