TLR2 agonist promotes myeloid-derived suppressor cell polarization via Runx1 in hepatocellular carcinoma

Abstract

Myeloid-derived suppressor cells (MDSCs) play a critical role in maintaining the tumor immune microenvironment; thus, the promotion of MDSC polarization will improve immunotherapies for cancers. However, the mechanisms involved in controlling MDSC polarization in hepatocellular carcinoma remain largely unclear. In this study, we found that injection of Pam3CSK4 attenuated the process of tumor growth, along with reduction of MDSC and recovery of T cell function. Moreover, Pam3CSK4 promoted MDSC polarization by targeting Runx1. Runx1 inhibitor reversed the therapeutic effect of Pam3CSK4 by increasing tumor size and weight and decreasing the survival rate of tumor mice. In addition, targeting Runx1 reduced the expression of CD11c, F4/80, CD80/CD86 and MHC-II in MDSC after Pam3CSK4 stimulation in vivo and in vitro. MDSC also exhibited consistent changes with increasing reactive oxygen species (ROS) production after Pam3CSK4 and Ro5-3335 treatment. RNA sequence data revealed that tfrc, steap3, and gclm were up-regulated in the Pam3CSK4/Ro5-3335 group compared with Pam3CSK4 treatment alone, suggesting that the regulatory effect of TLR2 and Runx1 on MDSC might act through the ferroptosis pathway. Overall, our study has identified a critical role for TLR2 and Runx1 in regulating the differentiation and function of MDSCs and has provided a new mechanism of controlling MDSC polarization during HCC immunotherapy.

Keywords: Hepatocellular carcinoma; MDSC; Runx1; TLR2 agonist; Tumor therapy.