Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling

Hui Liu,Chung Mau Lo,Wei Yi Zhang,Jie Zhou,Chang Chun Ling,Jiang Liu,Kwan Man,Wai Ho Oscar Yeung,Li Pang,Xin Xiang Yang,Xiao Bing Liu,Tak Pan Kevin Ng

doi:10.1038/s41419-021-03788-4

Abstract

Tumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.

Highlights

Liver transplantation offers an effective therapeutic treatment for selected patients with hepatocellular carcinoma (HCC), which is the third cause of cancer-related mortality worldwide[1,2]
Consistent with the results, the survival analysis demonstrated that the patients with GWR < 60% had poor disease-free survival compared to patients with GWR ≥ 60%, while no significant difference in overall survival after liver transplantation (Fig. 1A)
myeloid-derived suppressor cell (MDSC) were increased in HCC patients with small-for-size graft or tumor recurrence post-liver transplantation

Summary

Introduction

Liver transplantation offers an effective therapeutic treatment for selected patients with hepatocellular carcinoma (HCC), which is the third cause of cancer-related mortality worldwide[1,2]. Several liver transplantation centers reported that LDLT patients experienced. Liu et al Cell Death and Disease (2021)12:489 infiltrated into the liver in hepatic diseases[8,9]. CXCL10, with its receptor C-X-C motif chemokine receptor 3 (CXCR3), facilitates cancer cell proliferation, metastasis, and invasion[11,12,13]. CXCL10 contributes to inflammatory responses or hepatocellular apoptosis through toll-like receptor 4 (TLR4), but not CXCR314,15. The intestinal venous congestion caused by liver graft injury facilitated cancer recurrence by TLR4 increase in rodent models[16]. Few studies reported the mechanism of CXCL10/TLR4 signaling regulating immune cells for promoting liver cancer recurrence

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