miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+T cell infiltration
Files
(Published version)
Date
2023
Authors
Chen, R.
Coleborn, E.
Bhavsar, C.
Wang, Y.
Alim, L.
Wilkinson, A.N.
Tran, M.A.
Irgam, G.
Atluri, S.
Wong, K.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Molecular Therapy: Oncolytics, 2023; 31:100725-1-100725-15
Statement of Responsibility
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, and Sherry Y. Wu
Conference Name
Abstract
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<sup>+</sup> 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<sup>-/-</sup> 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<sup>-/-</sup> 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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).