Myeloid-derived suppressor cells mobilization through CXCL1-CXCR2 signaling facilitate tumor recurrence after liver transplantation

Abstract

Backgrounds and aims: Long-term survival of recipients of liver transplantation for the patients with hepatocellular carcinoma (HCC) is hindered by tumor recurrence. Emerging evidences confirm the immunosuppressive characteristics of myeloid-derived suppressor cells (MDSCs) and were accumulated in tumor microenvironment. However, its hepatic oncogenic mechanism remains poorly defined. Here we aim to investigate the role of MDSCs subpopulations on tumor recurrence. Methods: MDSCs of HCC patients who underwent liver resection and liver transplantation were analyzed by immunohistochemistry and flow cytometry. The underlying mechanism was further explored in mouse hepatic ischemia/reperfusion injury (IRI) model with major hepatectomy. Results: The significant enrichment of circulatory and intragraft MDSCs was observed in HCC recurrence patients who underwent liver transplantation and liver resection compared with those without recurrence (Fig.1&2A). Moreover, MDSCs accumulation in HCC patients was also significantly higher than healthy donors accompanied with decreased intratumoral CD8+ T cells (Fig.2B). Given the role of CXCL1 in tumorigenesis, the mRNA expression level of CXCL1 in tumor was highest in tumor followed by non-tumor tissues and healthy controls (Fig.3A). Upregulated CXCL1 was also found in a mouse hepatic IR model (Fig.3B). Furthermore, high level of CXCR2 expression was detected on MDSCs. It suggested that CXCL1-CXCR2 signaling may induce MDSC mobilization. Consistently, significantly higher frequencies of MDSC subpopulations in peripheral blood, paired tumor and non-tumor liver tissues were observed compared with healthy donors (Fig.4). Conclusion: CXCL1/CXCR2 signaling mobilized circulatory MDSCs which further promoted tumor recurrence after liver transplantation. The populations of circulatory MDSCs may predict HCC recurrence.