Chung, Charlie, Nizam, Aaron, Yueh, Brian, Subhash, Santhilal, Eskiocak, Onur, Frimer, Marina, Goldberg, Gary L, Beyaz, Semir (2023) Autologous patient-derived organoid-immune cell co-culture platform for therapeutic discovery in high-grade endometrial cancer. In: 114th Annual Meeting of the American Association for Cancer Research (AACR), APR 14-19, 2023, Orlando, FL.
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 rates upon chemotherapies, thus showing very poor prognosis. Immunotherapy revolutionized the field of cancer medicine, but the 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. The 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 are downregulated in HGEC organoids. qPCR assays confirmed that Major Histocompatibility Complexes (MHCs) are downregulated in HGEC organoids. The suppression of MHC expression could be reverted by external stimuli such as IFNg and Tazemetostat, an EZH2 inhibitor. 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 data show that HGEC organoids that were pre-treated with IFNg or Tazemetostat display a greater immune cell co-localization and immune cell-mediated apoptosis during the co-culture period. 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.
| Item Type: | Conference or Workshop Item (Poster) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > endometrial cancer diseases & disorders > cancer > drugs and therapies > Immunotherapy diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Beyaz lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2023 |
| Date Deposited: | 19 Sep 2023 18:50 |
| Last Modified: | 08 Jan 2024 18:26 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/40921 |
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