Abstract B077: Spatial patterns of immune cell states are associated with poor response to neoadjuvant chemotherapy in high-grade serous ovarian cancer
Authors: Niemiec Iga , Kahelin Essi , Liang Zhihan , Erkan Erdogan P. , Vähärautio Anna , Virtanen Anni , Färkkilä Anniina 
Published: March 2024

Abstract
The composition and functional state of the tumor microenvironment (TME) play a crucial role in determining the response to neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSC) patients. Understanding these complex interactions is essential for patient stratification and the development of novel combination therapies. With the advent of spatial transcriptomics technologies, studying the TME in terms of not only quantitative, qualitative, but also spatial aspects have become possible. This study aimed to investigate the spatial distribution and functional states of different cell types within the HGSC TME and their association with NACT response. We utilized 10 publicly available post-NACT HGSC 10x Visium spatial transcriptomics samples comprising patients with good (n=3), partial (n=2), and poor (n=5) responses to NACT. Each spot on Visium hematoxylin and eosin (H&E) slides have been manually annotated by a pathologist as tumor, mixed (both tumor and stroma morphology), stroma or other. Three zones of stroma in the tumor-stromal interface (TSI) were defined based on proximity to tumor/mixed spots (TSI1 closest to the tumor, followed by TSI2 and TSI3). Differential gene expression (DGE) analysis followed by overrepresentation analysis (ORA) was performed to characterize transcriptional pathway activity variations between tumor, TSI, and stromal spots. Notably, differential activity was observed in crucial pathways such as epithelial-mesenchymal transition, tumor necrosis factor alpha (TNF-α) signaling, and estrogen response both within spot types and across different NACT responses. Additionally, analysis of cell type distribution within the zones was conducted. UCell scores for HGSC TME cell type signatures were calculated for each spot, and cell type deconvolution was performed using the FindTransferAnchor method from the Seurat R package. Comparisons of mean UCell and deconvolution scores across spot types revealed substantial spatial variations in cell type composition, particularly for macrophages, fibroblasts, and plasma cells. Notably, these spatial distributions showed significant changes with the NACT response. For instance, macrophage scores were markedly higher in good responders and decreased with distance from the tumor. Fibroblast signatures were significantly elevated in good responders but only in proximity to the tumor, while plasma cell scores were notably elevated exclusively within tumor and mixed spots of good responders. Furthermore, selected functional properties of these cell types were examined by computing UCell scores for crucial pathways governing their biology. Collectively, our findings highlight substantial differences in TME composition depending on proximity to the tumor and NACT response. Macrophages, fibroblasts, and plasma cells exhibited the most prominent spatial patterns. These results underscore the importance of studying the TME within a spatial context to gain deeper insights into these intricate interactions, so important to the NACT response.
Citation Format: Iga Niemiec, Essi Kahelin, Zhihan Liang, Erdogan P. Erkan, Anna Vähärautio, Anni Virtanen, Anniina Färkkilä. Spatial patterns of immune cell states are associated with poor response to neoadjuvant chemotherapy in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B077.