Abstract PR08: High-grade serous ovarian tumor cells modulate natural killer cells to create an immune-tolerant microenvironment
Authors: Gonzalez Veronica D. , Chen Shih-Yu , Huang Ying-Wen , Delgado Antonio , Sachs Karen , Nolan Garry P. , Fantl Wendy J. 
Published: September 2020

Abstract
Although the immunogenicity of HGSOC is well documented, responses to immunotherapy for HGSOC have been disappointing. Therefore, a deeper understanding of the cell types within the HGSOC tumor immune microenvironment could assist in identifying predictive mechanistic biomarkers to select patients likely to gain the most benefit from immunotherapy. Since their discovery in 1975, natural killer (NK) cells, an innate immune cell type, have been recognized to possess potent antitumor activity. NK cells are mechanistically distinct from T lymphocytes in that their killing activity is not mediated by high-resolution antigen specificity but through intracellular signaling by multiple germline cell surface receptors with both killing and inhibitory activities. These dual effector functions endow NK cells with roles in both immune surveillance to eradicate tumor cells and conversely with the creation of an immune tolerant microenvironment facilitating tumor progression. The balance between activating and inhibitory cell surface NK receptors determines which of these functions dominates. We recently published the first mass cytometry (aka CyTOF) study of newly diagnosed HGSOC tumors that focused on the tumor cells. We have now analyzed the CyTOF data of the immune cell infiltrate for the same set of tumors. To examine relationships between tumor and immune cell types, we performed extensive pairwise correlation analyses. In addition to correlations between tumor cell types and exhausted T-cell subpopulations, we observed strong positive correlations between different NK cell subpopulations with both overall tumor cell abundance and with tumor cells coexpressing E-cadherin and vimentin (EV cells). The latter are likely undergoing epithelial-to-mesenchymal transition and contributing to tumor progression. Intriguingly, the phenotype of the NK cell subpopulations resembled decidual NK cells. Decidual NK cells play a critical role in early pregnancy by conferring immune tolerance toward the hemi-allogeneic fetus. Our analysis suggests that the same features of immune tolerance could be subverted for HGSOC tumor maintenance and/or progression from the epithelial to metastatic state. Herein, we identify the phenotypes of the NK cells infiltrating HGSOC tumors and integrate these data with our CyTOF analysis of NK receptor ligands expressed by the tumor cells. Furthermore, CyTOF analysis of cocultures between HGSOC tumor and NK cell lines provides mechanistic insight as to how HGSOC tumor cells might direct NK cell function to create an immunosuppressive environment favoring tumor survival. NK cells are now at the center of a variety of immunotherapeutic approaches to exploit their tumor cell-killing activity. The data from this study could provide critical information about unappreciated adversity within the tumor immune microenvironment, which needs to be overcome for optimizing NK cell-based immunotherapy.
This abstract is also being presented as Poster B57.
Citation Format: Veronica D. Gonzalez, Shih-Yu Chen, Ying-Wen Huang, Antonio Delgado, Karen Sachs, Garry P. Nolan, Wendy J. Fantl. High-grade serous ovarian tumor cells modulate natural killer cells to create an immune-tolerant microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR08.