Dataset Information

Novel ovarian cancer PD-1+ NK cell subsets, targetable by combined immune-checkpoint blockade

ABSTRACT: Ovarian cancer (OC) is the fifth leading cause of cancer-related death and High-Grade Serous Ovarian Carcinoma (HGSOC) is its most common histotype. Current therapies are ineffective, and most patients develop a recurrence within a few years. Moreover, if outstanding results can be obtained with immune-checkpoint blockade strategies (mainly PD-1/PD-L axis) in immunotherapeutic protocols for several aggressive tumors, clinical trials didn’t show good results with HGSOC patients so far. Here we analysed, by multiparametric flow cytometry, NK cells derived from peripheral blood, peritoneal fluid, tumor tissue, and metastatic tissue of a large cohort of HGSOC patients, in order to define how NK cells could be leveraged to improve HGSOC immunotherapy. We identified new PD-1+NK subsets occurring in HGSOC patients, but absent in healthy donors, characterized by a CD56dimNKG2A+KIR+/-NKp46+CD57low phenotype and ineffective anti-tumor response against autologous HGSOC cells. This impairment could be rescued by treatment with a combination of anti-PD-1/PD-Ls, NKG2A, and KIRs mAbs. PD-1+ NK cells were enriched in the metastatic niche and high levels of tumor-infiltrating PD-1+ NK cells correlate with a worse outcome, suggesting a role for PD-1 in metastatic promotion/progression. Our data demonstrate the existence of novel tumor-infiltrating PD-1+ NK cell subsets in HGSOC patients, which are inversely related to patient outcome, showing the importance of these NK subsets. These subsets show indeed impaired anti-tumor activity, which can be rescued by combined ICs blockade, paving the way for more successful NK cell-based immunotherapy in OC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255486 | GEO | 2025/09/03

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: Although immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human cancer and immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs, including immune checkpoint inhibitors (ICIs), which have demonstrated limited effectiveness in OC patients. Methods: We established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+ Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). We assessed the efficacy of PD-1 blockade with pembrolizumab in the SKOV-3 Luc Hu-mouse model. The immune profiles of the tumors were characterized using colorimetric immunostaining and flow cytometry. Additionally, we analyzed RNA-seq data to investigate the gene expression signature of pembrolizumab refractory tumors. Results: We confirmed tumor development in both OC cell lines within CD34+ Hu-mice. In these models, human lymphocyte and myeloid cell subsets were present in the tumors, draining lymph nodes, blood, and spleens. The SKOV-3 Luc tumor-bearing Hu-mice did not respond to pembrolizumab monotherapy. These tumors exhibited a high presence of tumor-infiltrating macrophages. Tumors in Hu-mice unresponsive to pembrolizumab showed a lower abundance of CD8+ T-cells, memory B cells, plasma cells, and a higher proportion of naïve M0 macrophages and mast cells compared to the PBS control. Furthermore, we identified 43 significantly enriched gene sets in these tumors. The differentially expressed genes (DEGs) were predominantly enriched in HDAC class I, RB1, KLF1/3, TCF21, MYD88, SMARCE1 target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts. Conclusion: Our xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer potential avenues to explore mechanisms of resistance to PD-1/PD-L1 blockade in OC.

Dataset Information

Novel ovarian cancer PD-1+ NK cell subsets, targetable by combined immune-checkpoint blockade

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets