PD-1+ NK cell subsets in high grade serous ovarian cancer: an indicator of disease severity and a target for combined immune-checkpoint blockade

Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women, with High-Grade Serous Ovarian Carcinoma (HGSC) representing the most aggressive and prevalent subtype. Despite promising results in other malignancies, immune checkpoint blockade has shown limited efficacy in HGSC, highlighting the need for alternative immunotherapeutic targets. We conducted an integrated analysis combining multiparametric flow cytometry, RNA sequencing, multiplex immunohistochemistry, and functional assays to characterize NK cells isolated from peripheral blood, peritoneal fluid, primary tumor tissue, and metastases in 60 HGSC patients. We identified a distinct population of PD-1⁺ NK cells enriched in HGSC tumors and metastatic sites but absent in healthy donors. These cells, characterized by a CD56dimNKG2A⁺KIR⁺/⁻NKp46⁺CD57low phenotype, displayed impaired cytotoxicity against autologous HGSC targets, correlating with poorer prognosis. Crucially, this dysfunction was reversible upon combined blockade of PD-1/PD-L1, NKG2A, and KIRs. Spatial and molecular profiling revealed that these cells localize within PD-L1⁺/HLA-E⁺ tumor niches, suggesting that immune suppression is spatially and molecularly coordinated. Transcriptomic analysis confirmed their altered functional state and highlighted actionable checkpoint targets. Our findings uncover a previously underappreciated population of dysfunctional PD-1⁺ NK cells in HGSC and demonstrate that their suppression is reversible through combinatorial checkpoint inhibition. These insights support the development of spatially-informed, NK-targeted immunotherapies for HGSC patients, particularly those resistant to T cell-based strategies.

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Publication Details

Journal
Journal of Experimental & Clinical Cancer Research
Published
2025-08-29
DOI
https://doi.org/10.1186/s13046-025-03508-2
Citations
2
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
1.59

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article

PD-1+ NK cell subsets in high grade serous ovarian cancer: an indicator of disease severity and a target for combined immune-checkpoint blockade

Fabrizio Loiacono, Silvia Pesce, F Rampinelli, Lorenzo Moretta et al.
2 citations
Journal of Experimental & Clinical Cancer Research
Immune Cell Function and Interaction
1.59
article

PD-1+ NK cell subsets in high grade serous ovarian cancer: an indicator of disease severity and a target for combined immune-checkpoint blockade

Fabrizio Loiacono, Silvia Pesce, F Rampinelli, Lorenzo Moretta, Domenico Mavilio, Gianluca Ubezio, Éric Vivier, Ornella Patrizi, Valentina Obino, Simona Sivori, Michele Paudice, Matteo Bozzo, Simona Candiani, Mariangela Rutigliani, Marco Greppi, Giovanna Tabellini, Laura Paleari, Emanuela Marcenaro, Ombretta Melaiu, Camilla Jandus, Martina Di Luca, Silvia Parolini, Patrizio Castagnola, Valerio Gaetano Vellone, Franco Gorlero, Andrea De Censi, Pascale André, Olive Daniel
article en
2 citations

Abstract

Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women, with High-Grade Serous Ovarian Carcinoma (HGSC) representing the most aggressive and prevalent subtype. Despite promising results in other malignancies, immune checkpoint blockade has shown limited efficacy in HGSC, highlighting the need for alternative immunotherapeutic targets. We conducted an integrated analysis combining multiparametric flow cytometry, RNA sequencing, multiplex immunohistochemistry, and functional assays to characterize NK cells isolated from peripheral blood, peritoneal fluid, primary tumor tissue, and metastases in 60 HGSC patients. We identified a distinct population of PD-1⁺ NK cells enriched in HGSC tumors and metastatic sites but absent in healthy donors. These cells, characterized by a CD56dimNKG2A⁺KIR⁺/⁻NKp46⁺CD57low phenotype, displayed impaired cytotoxicity against autologous HGSC targets, correlating with poorer prognosis. Crucially, this dysfunction was reversible upon combined blockade of PD-1/PD-L1, NKG2A, and KIRs. Spatial and molecular profiling revealed that these cells localize within PD-L1⁺/HLA-E⁺ tumor niches, suggesting that immune suppression is spatially and molecularly coordinated. Transcriptomic analysis confirmed their altered functional state and highlighted actionable checkpoint targets. Our findings uncover a previously underappreciated population of dysfunctional PD-1⁺ NK cells in HGSC and demonstrate that their suppression is reversible through combinatorial checkpoint inhibition. These insights support the development of spatially-informed, NK-targeted immunotherapies for HGSC patients, particularly those resistant to T cell-based strategies.

Journal of Experimental & Clinical Cancer ResearchVol. 44(1)
University of Rome Tor Vergata (IT), Centre National de la Recherche Scientifique (FR), Inserm (FR), Queen Mary University of London (GB), University of Milan (IT), Aix-Marseille Université (FR), Istituto Giannina Gaslini (IT), Ente Ospedaliero Ospedali Galliera (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Immunité et Cancer (FR), Ludwig Cancer Research (CH), Bambino Gesù Children's Hospital (IT), Gibraltar Health Authority (GI), Innate Pharma (France) (FR), Ospedale Policlinico San Martino (IT), Hôpital de la Timone (FR), IRCCS Humanitas Research Hospital (IT), University of Brescia (IT), University of Genoa (IT), University of Lausanne (CH)
Fondazione Umberto Veronesi
Good health and well-being
Openalex Percentile: Top 15%
Immune Cell Function and Interaction
1.59
DOIOpen Access PDFOpenAlex
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