Researchers led by Ludwig Lausanne’s Denarda Dangaj Laniti and Eleonora Ghisoni described in an August issue of Cancer Cell four immunologic subtypes of recurrent ovarian cancers, the relationship of each to DNA repair deficiency in the tumor and how each subtype evolves to resist therapy. The researchers found that tumors with DNA repair deficiencies, such as BRCA mutations, tend to be infiltrated with CD8+ T cells and respond better to chemotherapy. Networks of dendritic cells and T cells in these tumors, which support responses to immunotherapy, persist when the tumors recur. Such tumors resist chemotherapy and Olaparib, a standard therapy for BRCA-deficient ovarian cancer, by a mechanism involving COX/PGE2 signaling. Adding a COX inhibitor to standard therapy in these mice restored sensitivity to chemotherapy, extending survival significantly. That survival time doubled when immunotherapy was added to the regimen. DNA repair-proficient tumors, meanwhile, tend to be devoid of myeloid-T cell networks and recruit immunosuppressive macrophages to help them resist therapy. Denarda, Eleonora and colleagues show these macrophages express high levels of ApoE and Trem2, proteins involved in lipid metabolism. Targeting myeloid cells in such tumors with an antibody inhibitor of Trem2 improved responses to chemotherapy and delayed tumor recurrence in mouse models. The classification system developed in this study could also serve as a combined immunologic and genomic biomarker to guide ovarian cancer therapy.
Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer
Cancer Cell, 2025 August 11