miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration

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

doi:10.1016/j.omto.2023.09.001

miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8⁺ T cell infiltration

Mol Ther Oncolytics. 2023 Sep 13:31:100725. doi: 10.1016/j.omto.2023.09.001. eCollection 2023 Dec 19.

Authors

Rui Chen¹, Elaina Coleborn¹, Chintan Bhavsar¹, Yue Wang², Louisa Alim¹, Andrew N Wilkinson¹, Michelle A Tran³, Gowri Irgam¹, Sharat Atluri¹, Kiefer Wong¹, Jae-Jun Shim⁴, Siddharth Adityan¹, Ju-Seog Lee⁴, Willem W Overwijk⁵, Raymond Steptoe⁶, Da Yang², Sherry Y Wu¹

Affiliations

¹ School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
² Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
³ Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.
⁴ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Frazer Institute, University of Queensland, Brisbane, QLD 4102, Australia.

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⁺ 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.

Keywords: immunology; microRNAs; nanotherapeutics; ovarian cancer; tumor microenvironment.