Revisiting Genomic Instability, Tumor Microenvironment and Immune Response in High-Grade Serous Ovarian Cancer

Abstract

High-grade serous tubo-ovarian cancer is the most common and aggressive type of ovarian cancer characterized by extensive genomic instability and marked inter- and intra-patient tumor heterogeneity. Tumor-site specific signaling crosstalk between cancer cells and the tumor microenvironment influences different tumor ecosystems that drive therapy response and disease progression. Cancer cell-intrinsic genomic aberrations further contribute to the diversity of the tumor immune landscape. Homologous recombination deficiency is considered a key oncogenic driver in 50% of the cases underlying distinctive mechanisms of tumor evolution. The heterogenous character of the tumor microenvironment represents a major challenge to identify predictive biomarkers of therapy response and to stratify subgroups amenable to immunotherapies.

Keywords: genomic instability; high-grade serous ovarian cancer; immune response; tumor heterogeneity.

Fig. 1

Fig. 1 Homologous recombination repair pathway of double-strand breaks (for a detailed description see info box). Created with Biorender.com [rerif]

Fig. 2

Fig. 2 Graphical summary of factors determining tumor heterogeneity in HGSC. Spatial and temporal heterogeneity in HGSC is shaped by the tumor-intrinsic capacity to repair DNA damaged sites, mutational and gene expression signatures that are associated with HR repair gene defects, and crosstalk between tumor, stromal and immune cells in the tumor microenvironment with implications for prognosis and therapy outcome. Created with Biorender.com [rerif]