PD-1 blockade unleashes local hepatitis B virus-related B cell response inhibiting hepatocellular carcinoma

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• The efficacy of anti-PD-1 therapy in cancer is often attributed to effector T cell activation.
• Hepatocellular carcinoma (HCC) is a significant global health concern, and understanding treatment mechanisms is crucial.
• Perioperative anti-PD-1 therapy is being investigated for resectable recurrent HCC.

Purpose of the Study:

• To elucidate the mechanism of action of perioperative anti-PD-1 therapy in hepatocellular carcinoma.
• To identify distinct patient subtypes based on immune responses in the tumor microenvironment.
• To explore the role of B cell immunity and antibody responses in anti-PD-1 efficacy.

Main Methods:

• Dynamic single-cell multi-omics analysis of tumor microenvironments.
• Clonal antibody repertoire analysis.
• Spatially paired single-cell RNA sequencing (scRNA-seq) and B cell receptor (BCR)-sequencing.

Main Results:

• Two distinct subtypes of late-recurrence HCC patients were identified: T cell-dominant and B cell-dominant.
• Somatic hypermutation led to antibodies targeting hepatitis B virus core antigen (HBcAg) in B cell-dominant patients.
• HBcAg export triggered local B cell and antibody responses, leading to complement activation and anti-tumor activity.

Conclusions:

• Anti-PD-1 efficacy in HCC involves enhanced anti-viral B cell immunity within tertiary lymphoid structures (TLSs).
• High-affinity HBcAg-reactive antibodies promote complement-mediated anti-tumor activity.
• This study reveals a novel mechanism of anti-PD-1 therapy involving B cell-mediated immunity in HCC.