Single-Nucleus and Spatial Transcriptome Profiling Delineates the Multicellular Ecosystem in Hepatocellular Carcinoma...

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Hepatocellular carcinoma (HCC) is a primary liver cancer with limited treatment options.
• Hepatic arterial infusion chemotherapy (HAIC) is a promising strategy for HCC.
• The post-treatment tumor microenvironment after HAIC remains poorly understood.

Purpose of the Study:

• To characterize the multicellular ecosystem of HCC after HAIC treatment.
• To identify immune cell changes and cellular communication patterns post-HAIC.
• To explore the role of tertiary lymphoid structures (TLS) and specific T cell populations in response to HAIC.

Main Methods:

• Integrated single-nucleus RNA sequencing and spatial transcriptomics.
• Analysis of tumor samples from treatment-naïve and post-HAIC HCC patients.
• Characterization of immune cell subtypes, cellular communication, and TLS formation.

Main Results:

• Increased CD4+ T, CD20+ B, and dendritic cell populations were observed post-HAIC.
• HAIC treatment promoted the formation of tertiary lymphoid structures (TLS).
• Expansion of intermediate exhausted CD8+ T cells (PD-1+CD8+ Tex-int) with antitumor function was identified, accumulating within TLS.

Conclusions:

• HAIC significantly alters the HCC tumor ecosystem, enhancing immune cell infiltration and communication.
• TLS formation is promoted by HAIC and serves as a niche for immune cell interactions.
• PD-1+CD8+ Tex-int cells represent a potential biomarker for HAIC treatment response in HCC.