Peter K. Sorger

Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma

Abstract High-grade serous ovarian cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent IFN signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer. Significance: This study maps the immune response in FT precursors of HGSOC, highlighting localized IFN signaling, chromosomal instability, and competing immune surveillance and suppression along the progression axis. It provides an explorable public spatial profiling atlas for investigating precancer mechanisms, biomarkers, and early detection and interception strategies. See related commentary by Recouvreux and Orsulic, p. 1093