IDDF2021-ABS-0185 Overcome primary resistance to immune checkpoint blockade in hepatocellular carcinoma

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<h3>Background</h3> Although immune checkpoint blockade (ICB) such as anti-programmed cell death 1 or its ligand (anti-PD-1/PD-L1) has revolutionized the treatment paradigm for cancer patients, most hepatocellular carcinoma (HCC) patients did not show benefits in the clinical scenario. The aim of this study is to investigate the underlying mechanisms of immunotherapy resistance in HCC and explore therapeutic approaches for enhancing HCC immunotherapy. <h3>Methods</h3> Fibrosis-associated HCC mouse model was established by chemical induction and tumor inoculation. Non-alcoholic fatty liver disease (NAFLD)-associated HCC was established by high-fat high carbohydrate diet and tumor implantation. Integrated analysis of single-cell RNA sequencing and bulk RNA sequencing were applied to identify monocytic myeloid-derived suppressor cells (M-MDSC) signature genes. Immune profiles were determined by flow cytometry. <h3>Results</h3> We found M-MDSC was specifically enriched in non-responders and a protein phosphatase was identified as a novel signature gene in M-MDSC. Inhibition of this protein phosphatase suppressed M-MDSC expansion and reduced reactive oxygen species generation, which holds promise in ameliorating the immunosuppressive microenvironment for tumor eradication. To further improve HCC therapy in ICB manner, we found an elegant nanoparticle-parceled PD-L1 trap which was superior to the conventional antibody-mediated ICB therapy. This PD-L1 trap was more up taken by the fibrotic liver environment compared to the normal liver indicating it would be suitable for majority of HCC patients. Ultimately, the PD-L1 trap triggered robust anti-tumor response in both fibrotic HCC and NAFLD-associated HCC. Mechanistically, PD-L1 trap exerted potent immune-editing function by diminishing immunosuppressive cells and boosting CD8⁺ T cells infiltration to the tumor. Those tumor-infiltrating CD8⁺ T cells were more cytotoxic with augmented cytokines production. More importantly, improved survival was observed in PD-L1 trap-treated HCC. <h3>Conclusions</h3> We uncovered a novel target for immunosuppressive myeloid cells which was closely associated with immunotherapy resistance in HCC. Moreover, a novel ICB approach showed translational potential for treating HCC with the enhanced therapeutic effect but reduced toxicity. We anticipate providing more efficacious options for HCC patients with long-term benefits. Acknowledgements: This study is supported by HMRF (16170451, 07180556) and Li Ka Shing Foundation.