Objectives: This study aimed to investigate the efficacy and safety of transarterial chemoembolization (TACE) plus camrelizumab, a monoclonal antibody targeting programmed death-1, and apatinib for patients with intermediate and advanced hepatocellular carcinoma (HCC) in a real-world setting. Methods: A total of 586 HCC patients treated with either TACE plus camrelizumab and apatinib (combination group, n = 107) or TACE monotherapy (monotherapy group, n = 479) were included retrospectively. Propensity score matching analysis was used to match patients. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety in the combination group were described in comparison to monotherapy. Results: After propensity score matching (1:2), 84 patients in the combination group were matched to 147 patients in the monotherapy group. The median age was 57 years and 71/84 (84.5%) patients were male in the combination group, while the median age was 57 years with 127/147 (86.4%) male in the monotherapy group. The median OS, PFS, and ORR in the combination group were significantly higher than those in the monotherapy group (median OS, 24.1 vs. 15.7 months, p = 0.008; median PFS, 13.5 vs. 7.7 months, p = 0.003; ORR, 59.5% [50/84] vs. 37.4% [55/147], p = 0.002). On multivariable Cox regression, combination therapy was associated with significantly better OS (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.26–0.64; p < 0.001) and PFS (adjusted HR, 0.52; 95% CI, 0.37–0.74; p < 0.001). Grade 3 or 4 adverse events occurred in 14/84 (16.7%) and 12/147 (8.2%) in the combination and monotherapy groups, respectively. Conclusions: TACE plus camrelizumab and apatinib showed significantly better OS, PFS, and ORR versus TACE monotherapy for predominantly advanced HCC. Clinical relevance statement: Compared with TACE monotherapy, TACE plus immunotherapy and molecular targeted therapy showed better clinical efficacy for predominantly advanced HCC patients, with a higher incidence of adverse events. Key Points: • This propensity score–matched study demonstrates that TACE plus immunotherapy and molecular targeted therapy have a longer OS, PFS, and ORR compared with TACE monotherapy in HCC. • Grade 3 or 4 adverse events occurred in 14/84 (16.7%) patients treated with TACE plus immunotherapy and molecular targeted therapy compared with 12/147 (8.2%) patients in the monotherapy group, while no grade 5 adverse events were observed in all cohorts.

Background: Increased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial.Methods: The paraffin sections of tumor tissues were obtained from patients with liver cancer and examined by immunohistochemical staining to investigate the role of Trp metabolic enzymes. To further confirm the pro-tumor effects induced by TDO2, we established TDO2 overexpression SMC-7721 and HepG2 liver cancer cell lines, and western blotting, cell proliferation, and colony formation were evaluated. Meanwhile, liver cancer subcutaneous mice models were established, and the tumorigenic rates of SMC-7721 cells, tumor volume and survival of bearing mice were calculated. In addition, the survival data of liver cancer patients from The Cancer Genome Atlas (TCGA) database were downloaded to analyze the effect of TDO2 expression on the survival of patients with liver cancer.Results: Here, we showed that constitutive TDO2 expression gave rise to liver cancer through upregulation of Trp metabolism. And the TDO2 expression was positively correlated with the poor prognosis in liver cancer patients. TDO2 expression in tumor cells accounted for the release of kynurenine (Kyn), which activated aryl hydrocarbon receptor (AhR) to promote liver cancer cells proliferation. Mechanistically, we found that AhR expression contributed to the secretion of Interleukin-6 (IL-6), thereby promoting tumor cells proliferation through the STAT3 and NF-kB/TIM4 signals. Interrupt of AhR signals by PDM2 revealed improved outcomes in subcutaneous tumor-bearing mice.Conclusions: Together, our study showed that the TDO2/Kyn/AhR/IL-6 signaling pathway was a novel mechanism underlying the malignancy of liver cancer, and suggested that AhR signals might be a valuable therapeutic target for tumor therapy.

CD8+ T cells are key members of adaptive immunity against tumorigenesis. As subset of CD8+ T cells, effector T cells (Te) and memory T cells (Tm) have different biological activities. The former can kill tumor cells but come into apoptosis in a certain period and the latter is static with the ability of self-renewal. Previous studies showed that microRNAs (miRNA) played critical roles in regulating adaptive immunity. This study aimed to identify the different expression of miRNAs between Te and Tm cells in tumor-bearing mice and to sort out the target miRNAs which can be regulated to improve anti-tumor activities of CD8+ T cells.