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

I.-M Launonen,A Szabó,P A Konstantinopoulos,J Casado,U.-M Haltia,Z Maliga,K C Strickland,S Santagata,A D D’Andrea,A Färkkilä,N Lyytikäinen,K Elias,P K Sorger,J R Lin,B E Howitt,C A Jacobson,E A Anttila

doi:10.1038/s41467-022-28389-3

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.

Highlights

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
The platinum-free interval (PFI), calculated as the time from last platinum-based chemotherapy to tumor relapse, was significantly longer in patients with BRCA1/2mut tumors as compared to patients with HRwt tumors in this patient cohort (p = 0.02, log-rank test, HR 0.30, Fig. S1c)
Overall survival (OS) was not significantly different between the groups (p = 0.3, log-rank test, HR 0.38, Fig. S1d)

Summary

Introduction

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. BRCA1/2mut tumors have been predicted to contain more neoantigens than tumors with no alterations in genes of the HR pathway (HRwt)[6], harbor an increased number of tumor-infiltrating lymphocytes[6], and have an elevated PD-L1 expression as compared to HRproficient tumors[6,8]. Consistent with these findings, we recently reported enhanced responses to combination of PARP inhibitor plus PD-1 inhibitor in patients with HR-deficient tumors[9]. The interplay of tumor, immune and stromal cells of BRCA1/2 mutated tumors has not yet been described

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Conclusion