Inhibiting B-cell-mediated Immunosuppression to Enhance the Immunotherapy Efficacy in Hepatocellular Carcinoma.

Background: Immunotherapy is efficacious in hepatocellular carcinoma (HCC), but the benefits are limited to a minority of patients. Most HCC patients show resistance to immune checkpoint blockade (ICB). Agonists of the stimulator of interferon genes (STING), potent immune stimulators, showed limited effectiveness. Using preclinical models, we studied the mechanisms of resistance to ICB and STING agonism. Methods: Murine HCA-1 and RIL-175 HCCs were orthotopically grown in mice with underlying liver fibrosis, to mimic the presentation of human HCC. Established tumors were treated with a STING agonist (BMS-986301) or anti-PD1 ICB, and mice were followed to evaluate safety and efficacy, as well as the mechanisms of treatment resistance by RNA sequencing, flow cytometry, and immunofluorescence, B-cell depletion and T-cell immunoglobulin and mucin domain 1 (TIM-1) ICB. Results: Unbiased analyses of transcriptomic data from murine HCC tissues from ICB-treated mice showed an increased abundance of intratumoral CD8 Conclusion: Our findings demonstrate that B cells are associated with ICB- and STING-mediated therapy resistance, and that depleting B-cells or targeting TIM-1 enhances both innate and acquired therapeutic efficacy in HCC.