Article Text
PDF
Abstract
Background Tumor-associated macrophages have been well-recognized in the tumor microenvironment. We reported that M2-macrophages in peritumor tissue can promote hepatocellular carcinoma (HCC) invasiveness, leading to poor prognosis of patients (Yeung et al. J Hepatol 2015). Here, we aim to investigate the role of CCL11 in modulating CCR5+ M2-like macrophages in the tissue microenvironment of HCC.
Methods The expression of CCL11-CCR5 signaling and M2-like macrophage-specific markers in HCC were analyzed by qPCR and immunostaining. Their clinical relevance and prognostic value were analyzed by Pearson’s test and Kaplan-Meier test. The functions of macrophage activation and Treg induction were characterized in vitro and ex vivo. The post-operative therapeutic potential of anti-CCL11 for preventing HCC recurrence was characterized by an in vivo surgical orthotopic HCC resection model.
Results The levels of CCL11 were significantly upregulated in liver non-tumor tissue compared with tumor tissue and normal liver (IDDF2024-ABS-0204 Figure 1. Compared with CCL11 in tumor CCL11 in non tumor was significantly overexpressed and highly associated with HCC recurrence and poor prognosis (A)). Non-tumor CCL11 was significantly associated with HCC recurrence (IDDF2024-ABS-0204 Figure 1. Compared with CCL11 in tumor CCL11 in non tumor was significantly overexpressed and highly associated with HCC recurrence and poor prognosis (B)) and was a prognosis factor after liver resection (IDDF2024-ABS-0204 Figure 1. Compared with CCL11 in tumor CCL11 in non tumor was significantly overexpressed and highly associated with HCC recurrence and poor prognosis (C)). Overexpressed CCL11 was significantly associated with CCR5+CD206+ M2-like macrophages in non-tumor tissue (IDDF2024-ABS-0204 Figure 2. CCR5+CD206+M2-like macrophages in non tumor tissue was significantly associated with overexpressed CCL11 and poor survival of HCC patients after liver resection (A)). Moreover, HCC patients with high CCR5+CD206 + M2-like macrophage infiltrations were significantly associated with poor survival (IDDF2024-ABS-0204 Figure 2. CCR5+CD206+M2-like macrophages in non tumor tissue was significantly associated with overexpressed CCL11 and poor survival of HCC patients after liver resection (B)). In vitro, CCL11 enhanced the activation of CCR5+ M2-like macrophages (IDDF2024-ABS-0204 Figure 3. CCL11 enhanced the activation of immunosuppressive CCR5-M2-like macrophages (A)) and promoted its expression of immunosuppression markers - PDL1, TIM3 and IL10 (IDDF2024-ABS-0204 Figure 3. CCL11 enhanced the activation of immunosuppressive CCR5-M2-like macrophages (B)). Furthermore, CCL11-treated CCR5+CD206+M2-like macrophages promoted Tregs induction via ex vivo stimulation (IDDF2024-ABS-0204 Figure 3. CCL11 enhanced the activation of immunosuppressive CCR5-M2-like macrophages (C)). In vivo , post-operative inhibition of CCL11 could effectively prevent the recurrence of HCC after liver resection. At the end of observation, 100% of the control mice had an intrahepatic relapse, while one of the five mice also had an extrahepatic tumor. In the anti-CCL11 therapy group, 16.7% of mice had an intrahepatic relapse (IDDF2024-ABS-0204 Figure 4. Inhibition of CCL11 could prevent cancer recurrence after tumor resection).
Compared with CCL11 in tumor CCL11 in non tumor was significantly overexpressed and highly associated with HCC recurrence and poor prognosis
CCR5+CD206+M2-like macrophages in non tumor tissue was significantly associated with overexpressed CCL11 and poor survival of HCC patients after liver resection
CCL11 enhanced the activation of immunosuppressive CCR5-M2-like macrophages
Inhibition of CCL11 could prevent cancer recurrence after tumor resection
Conclusions Overexpressed CCL11 could promote CCR5+ M2-like macrophage activation, which might induce immunosuppression and tumor progression. And inhibition of CCL11 after liver resection could prevent the recurrence of HCC.