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Abstract
<p class="first" id="d8906372e115">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.
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