Spatial Profiling of Ovarian Clear Cell Carcinoma Reveals Immune-Hot Features

Ya-Ting Tai; Wei-Chou Lin; Jieru Ye; Denis T-H Chen; Ko-Chen Chen; Duncan Y-T Wang; Tuan Z Tan; Lin-Hung Wei; Ruby Y-J Huang

doi:10.1016/j.modpat.2024.100630

Spatial Profiling of Ovarian Clear Cell Carcinoma Reveals Immune-Hot Features

Mod Pathol. 2024 Oct 10;38(1):100630. doi: 10.1016/j.modpat.2024.100630. Online ahead of print.

Authors

Ya-Ting Tai¹, Wei-Chou Lin², Jieru Ye³, Denis T-H Chen⁴, Ko-Chen Chen³, Duncan Y-T Wang³, Tuan Z Tan⁵, Lin-Hung Wei¹, Ruby Y-J Huang⁶

Affiliations

¹ Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
³ School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁴ School of Medicine, College of Medicine, Keele University, Newcastle, United Kingdom.
⁵ Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore.
⁶ School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Electronic address: rubyhuang@ntu.edu.tw.

PMID: 39395637
DOI: 10.1016/j.modpat.2024.100630

Abstract

Ovarian clear cell carcinoma (OCCC) has a high incidence in Asia, with a frequent occurrence at an early stage, but without sufficient data on molecular stratification for high-risk patients. Recently, immune-hot features have been proposed as indicators of poor prognosis in early stage OCCC. Specific patterns of intratumoral heterogeneity associated with immune-hot features must be defined. NanoString Digital Spatial Profiling technology (Cold spring biotech corp.) was used to decipher the spatial distribution of the 18-plex protein panel. Regions of interest (ROIs) were collected based on the reference hematoxylin and eosin-stained morphology. Areas of illumination (AOIs) were defined according to the ROI segmentation using the fluorescence signals of the visualization markers pan-cytokeratin (PanCK), CD45, or DNA. Unsupervised hierarchical clustering of 595 AOIs from 407 ROIs showed that the PanCK segments expressed different combinations of immune markers, suggestive of immune mimicry. The following 3 immune-hot clusters were identified: granzyme B-high, immune signal-high , and immune-like cells; the following 2 immune-cold clusters were identified: fibronectin-high and immune checkpoint-high cells. In tumor samples at the International Federation of Gynecology and Obstetrics stage IC1/2 experiencing recurrence, there was an increased occurrence of PanCK+ AOIs with immune signal-high and immune-like cell groups in the papillary morphology surrounded by macrophage lineage tumor-infiltrating immune cells (TIIs). In contrast, for tumor samples at the International Federation of Gynecology and Obstetrics stage IC3/II with recurrence, PanCK+ AOIs were prevalent in the fibronectin-high group, particularly in those with a tubulocystic morphology surrounded by lymphoid lineage non-TIIs. Our study on the spatial profiling of early stage OCCC tumors revealed that the immune mimicry of tumor cells, presence of TIIs, and morphologic patterns were associated with recurrence, which switched during tumor progression.

Keywords: ovarian cancer; spatial profiling; tumor microenvironment; tumor-infiltrating immune cells.