Tumor-suppressing multi-enterobacteria and PD-1/PD-L1 immune checkpoint inhibitor combination improves the outcome of hepatocellular carcinoma therapy.

OBJECTIVE: Programmed death 1 (PD-1) and its ligand PD-L1 inhibitors and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies have been approved for the treatment of advanced hepatocellular carcinoma (HCC), but the response rates of these immunotherapy are not high, and they are easy to be resistant. Studies have shown that the gut microbiota can significantly influence immune responses and the efficacy of immune checkpoint inhibitors (ICIs). The aim of this study is to investigate whether the combination therapy of Tumor-Suppressing Multi-Enterobacteria (TSME) and PD-L1 inhibitor (atezolizumab) can improve the efficacy of immunotherapy-resistant hepatocellular carcinoma. METHODS: Patients with advanced liver cancer resistant to atezolizumab were treated with tumor suppressor TSME combined with atezolizumab, and the efficacy was evaluated. By establishing a tumor-bearing mouse model, the control group, InVivoMAb anti-mouse PD-1 monotherapy group, TSME group, and anti-PD-1 mab +TSME double drug group were set up. To evaluate whether the combination therapy enhances the antitumor effect, the proportion of T cells in the tumor microenvironment (TME) was analyzed by immunohistochemistry. RESULTS: Patients with clinically immuno-resistant hepatocellular carcinoma who were treated with TSME still had a PFS of about 7 months with continued atezolizumab treatment, and they were still in long-term survival. The in vivo model showed that TSME combined with αPD-1 promoted the efficacy of anti-PD-1 antibody immunotherapy by increasing the proportion of CD8(+) T cells and CD4(+) T cells in the tumor microenvironment and reducing the proportion of regulatory T cells (Tregs) compared with TSME alone or αPD-1 alone. The relative tumor inhibition rate (TGI) of αPD-1+TSME combination group was as high as 58.78% ± 7.55%. Tumor volume was lower in the αPD-1+TSME group than in the monotherapy group. CONCLUSION: Anti-tumor TSME combined with αPD-1 mAb may be a new strategy to improve the sensitivity of immune-resistant patients with advanced hepatocellular carcinoma to anti-PD-1 immunotherapy.