BACKGROUND: The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases. METHODS: RNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples. RESULTS: 1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome. CONCLUSIONS: Immunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.

Caryl and Israel Englander Institute for Precision Medicine New York City New York USA

CLIP Childhood Leukemia Investigation Prague Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Prague Czech Republic

Department of Dermatology Yale University School of Medicine New Haven Connecticut USA

Department of Gynecology and Obstetrics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Gynecology and Obstetrics Charles University 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Gynecology and Obstetrics Charles University Faculty of Medicine and University Hospital Hradec Kralove Czech Republic

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Pathology and Molecular Medicine Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Radiation Oncology Weill Cornell Medical College New York City New York USA

Genomics Core Facility EMBL Heidelberg Germany

INSERM U1138 Centre de Recherche des Cordeliers Paris France

Sandra and Edward Meyer Cancer Center New York City New York USA

Sorbonne Université Paris France

Sotio Prague Czech Republic

The Fingerland Department of Pathology Charles University Faculty of Medicine and University Hospital Hradec Kralove Czech Republic

Université de Paris Paris France

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