miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration
Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multip...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770523000700 |
| _version_ | 1827805983066292224 |
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| author | Rui Chen Elaina Coleborn Chintan Bhavsar Yue Wang Louisa Alim Andrew N. Wilkinson Michelle A. Tran Gowri Irgam Sharat Atluri Kiefer Wong Jae-Jun Shim Siddharth Adityan Ju-Seog Lee Willem W. Overwijk Raymond Steptoe Da Yang Sherry Y. Wu |
| author_facet | Rui Chen Elaina Coleborn Chintan Bhavsar Yue Wang Louisa Alim Andrew N. Wilkinson Michelle A. Tran Gowri Irgam Sharat Atluri Kiefer Wong Jae-Jun Shim Siddharth Adityan Ju-Seog Lee Willem W. Overwijk Raymond Steptoe Da Yang Sherry Y. Wu |
| author_sort | Rui Chen |
| collection | DOAJ |
| description | Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53−/− and IG10 murine HGSC models. Increasing miR-146a expression in tumors improved anti-tumor immune responses by decreasing immune suppressive neutrophils and increasing CTL infiltration. Mechanistically, miR-146a targets IL-1 receptor-associated kinase 1 and tumor necrosis factor receptor-associated factor 6 adaptor molecules of the transcription factor nuclear factor κB signaling pathway in ID8-p53−/− cells and decreases production of the downstream neutrophil chemoattractant, C-X-C motif chemokine ligand 1. In addition to HGSC, tumoral miR-146a expression also correlates strongly with CTL infiltration in other cancer types including thyroid, prostate, breast, and adrenocortical cancers. Altogether, our findings highlight the ability of miR-146a to overcome immune suppression and improve CTL infiltration in tumors. |
| first_indexed | 2024-03-11T21:34:55Z |
| format | Article |
| id | doaj.art-88542394fd9f4c9a9f44ff43addb21fd |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-03-11T21:34:55Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-88542394fd9f4c9a9f44ff43addb21fd2023-09-27T04:43:18ZengElsevierMolecular Therapy: Oncolytics2372-77052023-12-0131100725miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltrationRui Chen0Elaina Coleborn1Chintan Bhavsar2Yue Wang3Louisa Alim4Andrew N. Wilkinson5Michelle A. Tran6Gowri Irgam7Sharat Atluri8Kiefer Wong9Jae-Jun Shim10Siddharth Adityan11Ju-Seog Lee12Willem W. Overwijk13Raymond Steptoe14Da Yang15Sherry Y. Wu16School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaDepartment of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USASchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaIcahn School of Medicine, Mount Sinai, New York, NY 10029, USASchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USASchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAFrazer Institute, University of Queensland, Brisbane, QLD 4102, AustraliaDepartment of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USASchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; Corresponding author: Sherry Y. Wu, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53−/− and IG10 murine HGSC models. Increasing miR-146a expression in tumors improved anti-tumor immune responses by decreasing immune suppressive neutrophils and increasing CTL infiltration. Mechanistically, miR-146a targets IL-1 receptor-associated kinase 1 and tumor necrosis factor receptor-associated factor 6 adaptor molecules of the transcription factor nuclear factor κB signaling pathway in ID8-p53−/− cells and decreases production of the downstream neutrophil chemoattractant, C-X-C motif chemokine ligand 1. In addition to HGSC, tumoral miR-146a expression also correlates strongly with CTL infiltration in other cancer types including thyroid, prostate, breast, and adrenocortical cancers. Altogether, our findings highlight the ability of miR-146a to overcome immune suppression and improve CTL infiltration in tumors.http://www.sciencedirect.com/science/article/pii/S2372770523000700ovarian cancermicroRNAstumor microenvironmentnanotherapeuticsimmunology |
| spellingShingle | Rui Chen Elaina Coleborn Chintan Bhavsar Yue Wang Louisa Alim Andrew N. Wilkinson Michelle A. Tran Gowri Irgam Sharat Atluri Kiefer Wong Jae-Jun Shim Siddharth Adityan Ju-Seog Lee Willem W. Overwijk Raymond Steptoe Da Yang Sherry Y. Wu miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration Molecular Therapy: Oncolytics ovarian cancer microRNAs tumor microenvironment nanotherapeutics immunology |
| title | miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration |
| title_full | miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration |
| title_fullStr | miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration |
| title_full_unstemmed | miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration |
| title_short | miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration |
| title_sort | mir 146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing cd8 t cell infiltration |
| topic | ovarian cancer microRNAs tumor microenvironment nanotherapeutics immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2372770523000700 |
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