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

Immunotherapy benefits only a minority of hepatocellular carcinoma (HCC) patients due to immune checkpoint blockade (ICB) resistance, and agonists of the stimulator of interferon genes (STING) also showed limited efficacy despite their immune-stimulating properties. Here we show that increased intratumoral B cells mediate the resistance to ICB and STING agonism. In the preclinical models with liver fibrosis that mimic human HCCs, tumors treated by anti-PD-1 ICB or a STING agonist (BMS-986301) showed more B-cell infiltration. STING agonism increased circulating IL-10 and intratumoral infiltration by B cells, including B cells expressing T-cell immunoglobulin and mucin domain 1 (TIM-1), and promoted the formation of tertiary lymphoid structure (TLS)-like structures, especially in the peritumoral areas. Strikingly, adding B cell depletion to ICB or STING agonism treatment significantly increased survival. Unlike ICB, STING agonism also had a pronounced anti-metastatic activity. In addition, the combination of STING agonism and TIM-1 blockade augmented B cell differentiation and antigen presentation in vitro and improved the anti-tumor effects in murine HCC in vivo. This approach decreased TIM-1+ B cells in the tumor and shifted B cells to higher expression of CD86 and MHC class II, enhancing their antigen presentation capability and further boosting the antitumor efficacy of CD8+ cytotoxic T cells. 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. Overall design: Using murine tumor tissues and cultured B cells collected in a time-matched manner, we employed RNA-seq to evaluate the transcriptional changes in murine RIL-175 and HCA-1 hepatocellular carcinoma (HCC) tissues as well as in vitro cultured B cells isolated from spleen tissues after the treatment with STING agonist or immune checkpoint inhibitors or the combination.