miR-146a Inhibits Ovarian Tumor Growth In Vivo via Targeting Immunosuppressive Neutrophils and Enhancing CD8+ T Cell Infiltration

Authors

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

Publication Date

9-19-2023

Journal

Molecular Therapy - Oncolytics

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

ovarian cancer, microRNAs, tumor microenvironment, nanotherapeutics, immunology

Comments

Supplementary Material

PMID: 37781339

DOI

10.1016/j.omto.2023.09.001

PMID

37781339

PMCID

PMC10539880

PubMedCentral® Posted Date

September 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes