Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer
Eleonora Ghisoni, Fabrizio Benedetti, Aspram Minasyan, Mathieu Desbuisson, Paula Cunnea, Alizée J Grimm, Noémie Fahr, Charlotte Capt, Nicolas Rayroux, Flavia De Carlo, D. Gulhan, Julien Dagher, David Barras, Matteo Morotti, Juan A. Marín‐Jiménez, Bovannak Stewen Chap, Tania Santoro, Giulia Spagnol, Mapi Fleury, Katerina Fortis, Julien Dorier, Mary K. Townsend, Stephanie Tissot, Sylvie Rusakiewicz, Humberto J. Ferreira, Anne I. Kraemer, Michal Bassani-Stenberg, Elizabeth M. Swisher, L. Kandalaft, Spyridon Mastroyannis, Kathleen T. Montone, Daniel Powell, Susana Banerjee, Kathryn L. Terry, Shelley S. Tworoger, Mikaël J. Pittet, János L. Tanyi, George Coukos, Melissa A. Merritt, Christina Fotopoulou, José R. Conejo-García, Denarda Dangaj Laniti
Abstract
Immunotherapy has shown limited success in recurrent ovarian cancer (OC), with prognostic insights largely derived from treatment-naive tumors. We analyzed 697 tumor samples (566 primary and 131 recurrent) from 595 OC patients across five independent cohorts, capturing tumor-infiltrating lymphocytes (TILs) heterogeneity and identifying four immune phenotypes linked to prognosis and TIL:myeloid networks driving malignant progression. We found that in preclinical mouse models, mirroring inflamed human OCs, the recurrent Brca1 mut tumors maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through upregulation of COX/PGE 2 signaling. Conversely, recurrent Brca1 wt tumors displayed loss of TILs:DCs niches and accumulated immunosuppressive tumor microenvironment (TME) networks featuring Trem2/ApoE high tumor associated macrophages (TAMs) and Nduf4l2 high / Galectin3 high malignant states. Recurrent tumors recapitulate the immunogenic landscapes of original cancers. Our findings reveal BRCA-dependent TIL:myeloid crosstalk as key to persistent immunogenicity in recurrent OC and propose new targets to enhance chemotherapy efficacy.