The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer
IntroductionOvarian cancer (OC) is the sixth most common malignancy in women and the poor 5-year survival emphasises the need for novel therapies. NK cells play an important role in the control of malignant disease but the nature of tumour-infiltrating and peripheral NK cells in OC remains unclear.M...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1477781/full |
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| author | Rachel Pounds Rachel Pounds Wayne Croft Hayden Pearce Tasnia Hossain Kavita Singh Janos Balega David N. Jeevan Sudha Sundar Sudha Sundar Sean Kehoe Jason Yap Jason Yap Paul Moss Jianmin Zuo |
| author_facet | Rachel Pounds Rachel Pounds Wayne Croft Hayden Pearce Tasnia Hossain Kavita Singh Janos Balega David N. Jeevan Sudha Sundar Sudha Sundar Sean Kehoe Jason Yap Jason Yap Paul Moss Jianmin Zuo |
| author_sort | Rachel Pounds |
| collection | DOAJ |
| description | IntroductionOvarian cancer (OC) is the sixth most common malignancy in women and the poor 5-year survival emphasises the need for novel therapies. NK cells play an important role in the control of malignant disease but the nature of tumour-infiltrating and peripheral NK cells in OC remains unclear.MethodsUsing flow cytometric analysis, we studied the phenotype and function of NK cells in blood, primary tumour and metastatic tissue in 80 women with OC. The cell type contexture of metastatic OC tissue was explored utilising scRNAseq analysis, with a focus on portraying an immunogenic tumour microenvironment and determining the characteristics of a dysfunctional NK cell population.ResultsThe proportion of peripheral NK cells was markedly elevated with a highly activated profile and increased cytotoxicity. In contrast, NK cell numbers in primary tumour and metastasis were substantially reduced, with downregulation of activatory receptors together with elevated PD-1 expression. scRNA-Seq identified 5 NK cell subpopulations along with increased exhausted and immature NK cells within tumour tissue compared to normal tissue. These features were attenuated following chemotherapy where higher levels of activated and cytotoxic NK cells associated with improved disease-free survival. Correlation of NK cell phenotype with clinical outcomes revealed high levels of DNAM-1 expression on tissue-localised and peripheral NK cells to be associated with reduced survival. Expression of PVR, the DNAM-1 ligand, was significantly increased on tumours and DNAM-1 mediated NK cell lysis of primary tumour tissue was observed in vitro.DiscussionThese findings reveal profound modulation of the tumour tissue and systemic profile of NK cells which likely contributes to the high rates of local progression and metastasis seen with OC. Immunotherapeutic approaches that overcome local immune suppression and enhance DNAM-1-targeted lysis of OC offer the potential to improve disease control. |
| format | Article |
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| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-74f6c44ee3f34e0aab3a1f4f1f1c19662025-01-06T06:59:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14777811477781The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancerRachel Pounds0Rachel Pounds1Wayne Croft2Hayden Pearce3Tasnia Hossain4Kavita Singh5Janos Balega6David N. Jeevan7Sudha Sundar8Sudha Sundar9Sean Kehoe10Jason Yap11Jason Yap12Paul Moss13Jianmin Zuo14Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomPan-Birmingham Gynaecological Cancer Centre, City Hospital, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomPan-Birmingham Gynaecological Cancer Centre, City Hospital, Birmingham, United KingdomPan-Birmingham Gynaecological Cancer Centre, City Hospital, Birmingham, United KingdomInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomPan-Birmingham Gynaecological Cancer Centre, City Hospital, Birmingham, United KingdomOxford Gynaecological Cancer Centre, Churchill Hospital, Oxford University Hospitals Foundation Trust, Oxford, United KingdomInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomPan-Birmingham Gynaecological Cancer Centre, City Hospital, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomIntroductionOvarian cancer (OC) is the sixth most common malignancy in women and the poor 5-year survival emphasises the need for novel therapies. NK cells play an important role in the control of malignant disease but the nature of tumour-infiltrating and peripheral NK cells in OC remains unclear.MethodsUsing flow cytometric analysis, we studied the phenotype and function of NK cells in blood, primary tumour and metastatic tissue in 80 women with OC. The cell type contexture of metastatic OC tissue was explored utilising scRNAseq analysis, with a focus on portraying an immunogenic tumour microenvironment and determining the characteristics of a dysfunctional NK cell population.ResultsThe proportion of peripheral NK cells was markedly elevated with a highly activated profile and increased cytotoxicity. In contrast, NK cell numbers in primary tumour and metastasis were substantially reduced, with downregulation of activatory receptors together with elevated PD-1 expression. scRNA-Seq identified 5 NK cell subpopulations along with increased exhausted and immature NK cells within tumour tissue compared to normal tissue. These features were attenuated following chemotherapy where higher levels of activated and cytotoxic NK cells associated with improved disease-free survival. Correlation of NK cell phenotype with clinical outcomes revealed high levels of DNAM-1 expression on tissue-localised and peripheral NK cells to be associated with reduced survival. Expression of PVR, the DNAM-1 ligand, was significantly increased on tumours and DNAM-1 mediated NK cell lysis of primary tumour tissue was observed in vitro.DiscussionThese findings reveal profound modulation of the tumour tissue and systemic profile of NK cells which likely contributes to the high rates of local progression and metastasis seen with OC. Immunotherapeutic approaches that overcome local immune suppression and enhance DNAM-1-targeted lysis of OC offer the potential to improve disease control.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1477781/fullHGSOCNK cellsDNAM-1cancer immunologyovarian cancer |
| spellingShingle | Rachel Pounds Rachel Pounds Wayne Croft Hayden Pearce Tasnia Hossain Kavita Singh Janos Balega David N. Jeevan Sudha Sundar Sudha Sundar Sean Kehoe Jason Yap Jason Yap Paul Moss Jianmin Zuo The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer Frontiers in Immunology HGSOC NK cells DNAM-1 cancer immunology ovarian cancer |
| title | The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer |
| title_full | The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer |
| title_fullStr | The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer |
| title_full_unstemmed | The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer |
| title_short | The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer |
| title_sort | emergence of dnam 1 as the facilitator of nk cell mediated killing in ovarian cancer |
| topic | HGSOC NK cells DNAM-1 cancer immunology ovarian cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1477781/full |
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