Abstract Background: High-grade serous ovarian cancer (HGSC) typically originates in the Fallopian tube epithelium (FTE) and is characterized by genomic instability and near-universal TP53 defects. HGSC is typically diagnosed at an advanced stage and rapid progression once it becomes invasive. To date, immunotherapies have had limited efficacy in HGSC. Most current HGSC research focuses on tumor and immune profiling of fully fledged HGSC, where in the tumor microenvironment (TME) has already been established. Much less is known about the microenvironment of pre-neoplastic lesions and the role of the immune system in controlling HGSC emergence. Hence, there is an urgent need for in-depth research on the molecular interactions between precancerous cells and immune cells to better understand the process of malignant transformation and escape from host immunity. Method: By using our genetically defined, syngeneic organoid platform, FTE organoids were engineered to Trp53 -/-, Ccne1-overexpressing FTE organoids (“PC” organoids) and Brca1 +/- ;Trp53 -/- (PBrca1) and Brca2 -/- ;Trp53 -/- (PBrca2) to model Homologous recombination (HR) -deficient (HRD) and HR-Proficient (HRP) HGSC, respectively. Pre-tumor growth was monitored using an in vivo imaging system (IVIS) following luciferase-labeled precancerous cell ovarian bursal injection. In addition, adaptive transfer and antibody deletion were performed to determine which immune cell type (s) mediate immune surveillance. Results: In a previous study, our laboratory found that PC organoids are not tumorigenic in wild-type (WT) C57BL6 mice. In this study, I found that PC cells were eliminated around 1 month after bursal injection in WT mice. Surprisingly, however, they kept growing and eventually formed tumors in Rag2 -/- mice, which lack B and T lymphocytes. Then, T cells were adaptive transfer from WT mice bearing PC cells to Rag2 -/- mice. I observed a marked reduction in PC cell signal as early as 24 hours post-transfer, which suggests T cells play a critical role in the clearance of precancerous cells. I also found compared to PC cell, PBrca1 and PBrca2 FTE organoids, both of which are non-tumorigenic, are eliminated much earlier (in 24 hours) and was completed in rapidly (∼15 days) following bursal injection into both WT and Rag2 -/- mice. Following NK cells deletion in Rag2 -/- mice, I observed that PBrca1 cells successfully established growth, whereas PBrca2 cells exhibited significantly delayed clearance compared to the IgG control group. Additionally, compared to PC cells, the expression of mouse MHC-Ib Qa-1b, which inhibits NK cell–mediated cytotoxicity, was markedly reduced in PBrca1/2 cells. Although other explanations are possible, these data raise the possibility that PBrca1/2 cells elicit a strong NK cell mediated innate immune response. Conclusion: This study represents a novel and highly feasible approach to interrogating the pre-cancer TME. My findings demonstrate that HRD (PBrca1/2) and HRP (PC) trigger markedly divergent immune surveillance mechanisms during the pre-malignant phase. Citation Format: Jianmei Hou, Benjamin Neel. Organoid models reveal distinct mechanisms of pre-tumor immune surveillance in high grade serous ovarian cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr PR003.
Hou et al. (Fri,) studied this question.