Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis.

Jun-Long Zhao,Chun-Chen Gao,Ben-Chang Li,Yu-Chen Ye,Yi-Yang Hu,Peng-Fei Ma,Yong-Zhan Nie,Yan Chen,Liang Wang,Kai-Xi Ren,Shi-Qian Liang,Jia-Long Liang,Hong-Yan Qin,Xiao-Fei Li,Hua Han,Ru Jiang,Si-Jun Hu,Jian Bai,Wei Zhang

doi:10.1016/j.celrep.2022.110451

Abstract

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) play critical roles in tumorigenesis. However, the mechanisms underlying MDSC and TAM development and function remain unclear. In this study, we find that myeloid-specific activation of Notch/RBP-J signaling downregulates lactate transporter MCT2 transcription via its downstream molecule Hes1, leading to reduced intracellular lactate levels, blunted granulocytic MDSC (G-MDSC) differentiation, and enhanced TAM maturation. We identify c-Jun as a novel intracellular sensor of lactate in myeloid cells using liquid-chromatography-mass spectrometry (LC-MS) followed by CRISPR-Cas9-mediated gene disruption. Meanwhile, lactate interacts with c-Jun to protect from FBW7 ubiquitin-ligase-mediated degradation. Activation of Notch signaling and blockade of lactate import repress tumor progression by remodeling myeloid development. Consistently, the relationship between the Notch-MCT2/lactate-c-Jun axis in myeloid cells and tumorigenesis is also confirmed in clinical lung cancer biopsies. Taken together, our current study shows that lactate metabolism regulated by activated Notch signaling might participate in MDSC differentiation and TAM maturation.

Highlights

Tumor-associated myeloid cells, which primarily consist of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), modulate the tumor microenvironment (TME) and play critical roles in tumor progression and patient prognosis (Biswas et al, 2013; Gabrilovich et al, 2012)
The total number of infiltrated myeloid cells (CD11b+) and MDSCs, including granulocytic MDSC (G-MDSC) (Ly6GhiLy6CloCD11b+) and monocytic MDSCs (M-MDSCs) (Ly6GloLy6ChiCD11b+), was significantly increased in 3-week tumors compared with 2-week tumors
CD11c and Vcam1 are considered markers of mature macrophages and are associated with M1 macrophage polarization (Franklin et al, 2014; Ye et al, 2019b). Consistent with these findings, the results of our study showed that CD11c and Vcam1 levels were increased in mature TAMs (ma-TAMs) (Figure 1D)

Summary

Introduction

Tumor-associated myeloid cells, which primarily consist of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), modulate the tumor microenvironment (TME) and play critical roles in tumor progression and patient prognosis (Biswas et al, 2013; Gabrilovich et al, 2012). MDSCs are immature and pathologically activated myeloid cells that are subclassified into monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs). These two MDSC subsets possess distinct phenotypes and functional characteristics to suppress the immune response (Bronte et al, 2016). Studies by Gabrilovich and colleagues indicate that M-MDSCs differentiate into G-MDSCs in tumor culture medium (Mastio et al, 2019; Youn et al, 2013). Based on these studies, M-MDSCs can be converted into TAMs or G-MDSCs in the TME. The detailed mechanisms modulating these cell fates remain unclear

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Conclusion