A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68⁺ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8⁺ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4⁺ and CD8⁺ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8⁺ T cells in HCC.

Han JH, et al. Ann Surg Treat Res. 2014 Apr;86(4):184-191. https://doi.org/10.4174/astr.2014.86.4.184

Background and Aims: Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment. IgA contributes to inflammation and dismantling antitumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in Pil Soo Sung the tumor microenvironment of HCC. Approach and Results: CAF dynamics in HCC tumor microenvironment were analyzed through single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of patients with advanced HCC treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels (p<0.05). Single-cell analysis showed that subcluster proportions in the CAF-fibroblast activation protein-α matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of fibroblast activation protein in the CD68⁺ cells from patients with high serum IgA levels (p<0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 expression levels than those in mock-treated CAFs (p<0.05). Coculture with CAFs attenuated the cytotoxic function of activated CD8⁺ T cells. Interestingly, activated CD8⁺ T cells cocultured with IgA-treated CAFs exhibited increased programmed death-1 expression levels than those cocultured with mock-treated CAFs (p<0.05). Conclusions: Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T-cell function. Our study highlighted their potential roles in tumor progression and immune suppression.

BACKGROUND The aim of this study was to define the best curative strategy in patients with hepatocellular carcinoma (HCC) in a hepatitis B virus (HBV)-endemic region where living donation dominates the type of cadaveric donation for liver transplantation (LT). MATERIAL AND METHODS A retrospective cohort comprised those patients whose clinical course could potentially be traced for at least 10 years. We found 262 HCC patients who had undergone curative surgical treatment from March 1997 to August 2006. Among these patients, 156 were treated with liver resection (LR) (R group) and 106 patients underwent LT (T group, 100 patients with living donor). Tumor characteristics, overall survival (OS), and recurrence-free survival (RFS) were analyzed. RESULTS Postoperative mortality was not significantly different between the groups, whereas recurrence rate during the study period (until August 2016) was higher in the R group (56% in the R group versus 19% in the T group, p<0.001). The 10-year and 15-year OS and RFS were better in the T group. Subgroup analysis with patients having solitary and £5 cm tumor by preoperative imaging showed that the 10-year and 15-year OS and RFS were much better in the T group, irrespective of their preoperative liver function defined by MELD score. In the T group, resection as the surgical procedure and tumor size on histology were poor prognostic factors for RFS. Importantly, this superiority of LT over LR in OS and RFS applied only to the patients with relatively low preoperative alpha-fetoprotein (AFP) levels (AFP <100 ng/mL), because patients with higher levels compared with lower levels of AFP tended to have more recurrent tumors after LT, but not in the case of LR during long-term follow-up. CONCLUSIONS Overall, LT was associated with better survival outcomes than resection in patients with HCC in Korea, where living donation is a main transplant source.