Single-cell spatial atlas of high-grade serous ovarian cancer unveils MHC class II as a key driver of spatial tumor ecosystems and clinical outcomes

Abstract

The tumor microenvironment (TME) is a complex network of interactions between malignant and host cells, yet its orchestration in advanced high-grade serous ovarian carcinoma (HGSC) remains poorly understood. We present a comprehensive single-cell spatial atlas of 280 metastatic HGSCs, integrating high-dimensional imaging, genomics, and transcriptomics. Using 929 single-cell maps, we identify distinct spatial domains associated with phenotypically heterogeneous cellular compositions, and demonstrate that immune cell co-infiltration at the tumor-stroma interface significantly influences clinical outcomes. To uncover the key drivers of the tumor ecosystem, we developed CEFIIRA (Cell Feature Importance Identification by RAndom forest), which identified tumor cell-intrinsic MHC-II expression as a critical predictor of prolonged survival, independent of clinicomolecular profiles. Validation with external datasets confirmed that MHC-II-expressing cancer cells drive immune infiltration and orchestrate spatial tumor-immune interactions. Our atlas offers novel insights into immune surveillance mechanisms across HGSC clinicomolecular groups, paving the way for improved therapeutic strategies and patient stratification.

Competing Interest Statement

P.K.S. is co-founder and member of the BOD of Glencoe Software, is a member of the SAB for RareCyte, NanoString, Reverb Therapeutics and Montai Health, and consults for Merck; he holds equity in Glencoe and RareCyteGS reports institutional research support from Agendia, AstraZeneca, Biovica, Merck, Novartis, Roche, and Seagen. KVdV reports an advisory role for AstraZeneca, GSK, Owkin, and Exact Sciences, with financial compensation paid to the institute.