CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation

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• 作者：Chang Xian Li¹ ; ^&dagger ; ; Chang Chun Ling¹ ; ⁴ ; ^&dagger ; ; Yan Shao¹ ; Aimin Xu⁵ ; Xiang Cheng Li⁶ ; Kevin Tak-Pan Ng¹ ; ³ ; Xiao Bing Liu¹ ; Yuen Yuen Ma¹ ; Xiang Qi¹ ; Hui Liu¹ ; Jiang Liu¹ ; Oscar Wai Ho Yeung¹ ; Xin Xiang Yang¹ ; ⁶ ; Qing Sheng Liu¹ ; Yin Fan Lam¹ ; Yuan Zhai⁷ ; Chung Mau Lo¹ ; ² ; ³ ; Kwan Man¹ ; ² ; ³ ; ^{kwanman@hku.hk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HCC ; hepatocellular carcinoma ; IR ; ischemia reperfusion ; LDLT ; Living donor liver transplantation ; TLR4 ; Toll-like receptor 4 ; CXCL10 ; C-X-C motif chemokine 10 ; Tregs ; regulatory T cells ; SFS ; small-for-size ; OLT ; orthotopic liver transplantation ; CD279 ; the programmed death-1 receptor ; MFI ; mean fluorescence intensity
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：65
• 期：5
• 页码：944-952
• 全文大小：1352 K

文摘

Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation.

Methods

The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10^−/− and CXCR3^−/− mice models with hepatic IR injury.

Results

Clinically, patients received the graft with graft weight ratio (GWR) <60% had higher HCC recurrence after liver transplantation than the recipients with GWR ⩾60% graft. More circulating Tregs and higher intragraft TLR4/CXCL10/CXCR3 levels were detected in recipients with GWR <60% graft. These results were further validated in rat transplantation model. Foxp3⁺ cells and expressions of TLR4, CXCL10, TGFβ, CTLA-4 and CD274 were increased in rat liver tumor tissues from small-for-size graft group. In mouse model, the mobilization and recruitment of Tregs were decreased in TLR4^−/−, CXCL10^−/− and CXCR3^−/− mice compared to wild-type mice. Moreover, less CXCR3⁺ Tregs were recruited into liver in CXCL10^−/− mice after hepatic IR injury. The knockout of CXCL10 and depletion of Tregs inhibited tumor recurrence after hepatic IR injury.

Conclusion

CXCL10/CXCR3 signaling upregulated at liver graft injury directly induced the mobilization and intragraft recruitment of Tregs, which further promoted HCC recurrence after transplantation.

Lay summary

There were positive correlation among tumor recurrence, circulating Tregs and liver graft injury after human transplantation for HCC patients. The knockout of CXCL10 decreased hepatic recruitment of CXCR3⁺ Tregs and late phase tumor recurrence after hepatic IR injury.