Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

• Published in: Nature communications Vol. 13; no. 1; pp. 835 - 14
• Main Authors: Launonen, I.-M., Lyytikäinen, N., Casado, J., Anttila, E. A., Szabó, A., Haltia, U.-M., Jacobson, C. A., Lin, J. R., Maliga, Z., Howitt, B. E., Strickland, K. C., Santagata, S., Elias, K., D’Andrea, A. D., Konstantinopoulos, P. A., Sorger, P. K., Färkkilä, A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/105; 14/63; 631/67/1517/1709; 631/67/327; 631/67/580/1884; 692/4028/67/1517/1709; 692/4028/67/580/1884; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Breast cancer; Cancer; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - immunology; CD4 antigen; CD4-Positive T-Lymphocytes; CD8 antigen; CD8-Positive T-Lymphocytes; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - immunology; DNA repair; Female; Genes; Genes, BRCA1; Genes, BRCA2; Genotype; Homologous Recombination; Homology; Humanities and Social Sciences; Humans; Image analysis; Image processing; Immunofluorescence; Immunosurveillance; Lymphocytes T; multidisciplinary; Multiplexing; Mutation; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Phenotypes; Prognosis; Proteomics; Science; Science (multidisciplinary); Spatial analysis; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28389-3

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 ( BRCA1/2 mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2 mut 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  BRCA1/2 mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC. The tumour microenvironment has not been fully characterised in high-grade serous ovarian cancers (HGSOC). Here, the authors use highly multiplexed imaging to analyse the HGSOC immune microenvironment at spatial and single-cell resolution, with clinically relevant findings for BRCA1/2-mutated tumours.