Abstract 5656: Longitudinal spatial profiling reveals chemoresistance mechanisms and characteristics of minimal residual disease in high-grade serous ovarian cancer
Authors: Dai Yibo , Knisely Anne , Lawson Barrett Craig , Lee Sanghoon , Wani Khalida M. , Segura Rossana N. Lazcano , Melendez Brenda , Chen Jianfeng , Liu Yunhe , Chelvanambi Manoj , Gibson Laura A. , Johnson Sarah B. , Yeh Chih-Chen , Ingram Davis R. , Hudgens Courtney W. , Cho Kyung Serk , Pei Guangsheng , Jiang Jiahui , Chu Yanshuo , Lazar Alexander J. , Gao Jianjun , Wargo Jennifer , Wang Linghua , Jazaeri Amir A. 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy globally. Despite an initial response to upfront surgery and platinum-based chemotherapy in most cases, over 70% will relapse. A critical source of recurrence is minimal residual disease (MRD), which persists after upfront treatment yet is clinically undetectable. In this study, we performed second look laparoscopy (SLL) on advanced stage HGSOC patients who had received neoadjuvant chemotherapy (NACT) followed by interval debulking surgery and adjuvant chemotherapy and were in complete clinical remission by imaging and CA-125 tumor marker. Surgical MRD status was determined by pathological review of SLL biopsies. Matched samples from pre-treatment biopsy, interval debulking surgery and SLL in 4 MRD+ and 3 MRD- cases were analyzed using GeoMx Digital Spatial Profiling. Among them, samples from 1 MRD+ and 1 MRD- case were also profiled with Visium. The tumor cells of MRD+ cases exhibited stronger signaling related to hypoxia, angiogenesis, and epithelial-mesenchymal transition at baseline as well as diminished apoptosis signaling after NACT. In addition, progressively upregulated expressions of ATP binding cassette transporters were also observed over time in the tumor compartment of MRD+ cases, potentially contributing to chemoresistance. In the tumor microenvironment, MRD- cases displayed increased abundance of plasma cells, conventional dendritic cells and lymphocytes in both pre-treatment and interval debulking samples compared to MRD+ cases. Notably, Visium data of the MRD- case revealed tertiary lymphoid structures (TLS) in the pre-treatment sample, which became better organized following NACT, with plasma cells disseminating into adjacent tumor areas. Conversely, TLS were fewer and poorly organized in the MRD+ case. Longitudinal comparison of the 3 timepoints in MRD+ cases revealed more regulatory T cells in the stromal compartments of the MRD lesions. Furthermore, from Visium data, exclusion of CD8 T and plasma cells from the tumor core was evident in the MRD lesion. In line with this, strong TGF-β, IL-1β, IL6 and FGF2 signaling surrounding the tumor were noted, likely contributing to immune exclusion. The spatial distribution of multiple immune checkpoint molecules highly overlapped with that of CD8 T cells, indicating T cell exhaustion in the MRD lesion. In summary, these data suggested distinct cancer phenotypic states and immune features in surgically detected MRD+ HGSOC, shedding light on potential chemoresistance and immune evasion mechanisms that contribute to the MRD phase of disease. This study represents the first systemic characterization of ovarian cancer MRD by leveraging SLL, providing insights for designing personalized therapies aimed at eradicating these chemoresistant lesions and ultimately preventing disease recurrence.
Citation Format: Yibo Dai, Anne Knisely, Barrett Craig Lawson, Sanghoon Lee, Khalida M. Wani, Rossana N. Lazcano Segura, Brenda Melendez, Jianfeng Chen, Yunhe Liu, Manoj Chelvanambi, Laura A. Gibson, Sarah B. Johnson, Chih-Chen Yeh, Davis R. Ingram, Courtney W. Hudgens, Kyung Serk Cho, Guangsheng Pei, Jiahui Jiang, Yanshuo Chu, Alexander J. Lazar, Jianjun Gao, Jennifer Wargo, Linghua Wang, Amir A. Jazaeri. Longitudinal spatial profiling reveals chemoresistance mechanisms and characteristics of minimal residual disease in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5656.