Novel ovarian cancer PD-1+ NK cell subsets, targetable by combined immune-checkpoint blockade
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ABSTRACT:
PROVIDER: PRJNA1075099 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-09-03 | GSE255486 | GEO
Project description:It is known that NK cells are a heterogeneous population of functionally distinct NK cell subsets. Here we report on different genomic, phenotypic and functional properties of four murine NK cell subsets distinguished by CD117 (c-kit), CD27 and CD11b expression. Gene expression was measured in NK cell subsets freshly sorted from murine C57Bl/6 splenocytes. Two to three different batches were analysed.
2016-04-01 | E-GEOD-45842 | biostudies-arrayexpress
Project description:It is known that NK cells are a heterogeneous population of functionally distinct NK cell subsets. Here we report on different genomic, phenotypic and functional properties of four murine NK cell subsets distinguished by CD117 (c-kit), CD27 and CD11b expression.
2016-04-01 | GSE45842 | GEO
Project description:It is known that natural killer (NK) cells are a heterogeneous population of functionally distinct NK cell subsets. Here we report on different genomic, phenotypic and functional properties of human NK cell subsets derived from peripheral blood, thymus and bone marrow. NK cell subpopulations were defined via expression of CD56 and CD16.
2017-01-01 | GSE57479 | GEO
Project description:RNA expression of memory NK subsets
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Project description:In this study we have compared the proteomic profile of subsets of extracellular vesicles (EVs) prepared from the human NK cell line NK-92 cultured for 48hrs in serum-free conditions supplemented with 10 ng/ml human recombinant IL-15. The aim was to isolate and define an EV subset with cytolytic activity against tumor cells. Fort his purpose, bulk EVs were separated according to size (via size exclusion chromatography; SEC) or density (density gradient ultracentrifugation; DG-UC).
2022-09-09 | PXD034603 | Pride
Project description:Background: T cell-based immunotherapies including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells can induce durable responses in cancer patients. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of Natural Killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their Major Histocompatibility Complex class I (MHC I) expression due to acquired resistance mechanisms.
However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy.
Method: In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compound on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated utilizing compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types.
Results: The screening approach led to the identification of a Cbl-b inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with TIGIT blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells.
Conclusion: These findings underscore the relevance of Cbl-b inhibition in overcoming NK cells dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for cancer patients.
2024-08-12 | MSV000095572 | MassIVE
Project description:NK cells are lymphocytes that provide a first defense against viral infections and cancer. They act (i) cytotoxic by killing virus-infected and tumorigenic cells and (ii) immune regulatory by releasing cytokines and chemokines. These innate immune cells are commonly further classified as CD56bright and CD56dim NK cells. Former studies confirmed immune regulatory CD56bright NK cells as progenitors of cytotoxic CD56dim NK cells. CD57 was previously described as T cell marker for senescence and terminal differentiation. Recent studies detected CD57+ and CD57- NK cells among the CD56dim NK cell population and suggested a fully mature developmental status for CD57+ NK cells. The recent NK cell maturation model includes CD34+ hematopoietic stem cells (HSC), which develop into CD56bright NK cells, later into CD56dimCD57- and finally into terminally maturated CD56dimCD57+ (1) (2) (3). The molecular mechanisms of human NK cell differentiation and maturation remain unknown to this date. We performed for the first time a proteomic analysis of these distinct developmental stages of human primary NK cells, isolated from overall 10 healthy human blood donors. CD56bright NK cells versusCD56dim and CD56dimCD57- versus CD56dimCD57+ NK cells were analyzed by using quantitative peptide sequencing, which revealed individual protein signatures (3400 proteins) of these different NK cell developmental stages. Notably, our data support the current NK cell differentiation model by highlighting both strong distinctions between CD56dim/bright NK cells and close relationships between CD57+/- NK cells on the proteomic level. Among the most prominent and conserved regulated proteins, we detected myosin IIa, Calvasculin and Calcyclin with very similar expression patterns. We investigated their sub-cellular localization and observed specific recruitment- and accumulation-events at the NK cell immunological synapse (NKIS) after NK activation.
2013-01-23 | PRD000666 | Pride
Project description:The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we have described the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins following cytomegalovirus (CMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between CMV-associated adaptive NK cells and cytotoxic effector T cells, but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.
2015-03-06 | GSE66563 | GEO
Project description:We report the expression profiles of 21 T- and NK-cell lymphomas to provide a platform for further investigation of targetable vulnerabilities in diseases represented by these cell lines
2019-04-12 | GSE114085 | GEO