Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer
Inga-Maria Launonen, Nuppu Lyytikäinen, Julia Casado, Ella Anttila, Angéla Szabó, U.-M. Haltia, Connor A. Jacobson, Jia‐Ren Lin, Zoltan Maliga, Brooke E. Howitt, Kyle C. Strickland, Sandro Santagata, Kevin M. Elias, Alan D. D’Andrea, Panagiotis A. Konstantinopoulos, Peter K. Sorger, Anniina Färkkilä
Abstract
The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.