Δ42PD-1 expressed M2 macrophages promoted tumor recurrence after liver transplantation

Abstract

Δ42PD-1 expressed M2 macrophages promoted tumor recurrence after liver transplantation Introduction Tumor recurrence remains to be a major challenge for liver transplantation for the patients with hepatocellular carcinoma. We previously reported that a subpopulation of macrophages (M2) led to poor recurrence-free survival in HCC patients received curative hepatectomy. The significances and activation mechanisms of these cells in liver transplantation are unknown. Preliminary evidences indicated the accumulation of a subset of M2 macrophages, expressed with Δ42PD-1, a natural isoform of a key immune regulator PD-1, in post-transplant tissues. We hypothesized that liver graft injury during transplantation may activate M2 macrophages, via Δ42PD-1 mechanism, lead to tumor recurrence. Materials and Methods In clinical study, the expressions level of intra-graft M2 macrophages with/without Δ42PD-1 were examined followed by the association analyses with patients’ post-transplant parameters. The tumor promoting mechanisms of M2 macrophages and Δ42PD-1 were investigated in rat tumor transplant model and in vitro co-cultivation studies. Results Clinically, 2.1-fold increased of intra-graft M2 macrophages were found in living donor compared to deceased donor liver transplantation (Figure-1). Moreover, Δ42PD-1 was found to be highly expressed in these cells (Figure-2). In terms of clinical significances, M2 macrophages contributed to the higher recurrence incidence and shorter recurrence-free survival in HCC recipients (Figure-3A-B). In vivo study showed that liver graft injuries significantly induced the accumulation of M2 macrophages after transplantation and resulted in larger tumor volume in the rat transplant tumor model (Figure-4). Δ42PD-1[high] macrophages expressed characteristic M2 phenotypes including pro-tumor cytokine secretory profiles compared to Δ42PD-1[low] cells. Conclusion We revealed a novel cellular mechanism of the post-transplant recurrence in liver transplantation. Liver graft injury induced the accumulation and activation of tumor promoting Δ42PD-1 M2 macrophages. Targeting the specific population represent a potential therapeutic strategy in attenuating HCC tumor recurrence.