Tumor-Infiltrating mregDCs Restrain Anti-Tumor Immunity in Early Relapse HCC

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• The tumor microenvironment (TME) is crucial in hepatocellular carcinoma (HCC) progression.
• The specific mechanisms by which myeloid cells contribute to HCC relapse remain largely unknown.

Purpose of the Study:

• To investigate the role of myeloid cells in driving HCC relapse.
• To identify novel therapeutic targets for HCC immunotherapy.

Main Methods:

• Utilized full-length single-cell RNA sequencing (scRNA-seq) on primary and early-relapse HCC patient samples.
• Conducted in vivo mouse models to test therapeutic interventions.

Main Results:

• Identified a mature, immunoregulatory dendritic cell subset (mregDCs) in relapsed HCC.
• Discovered that mregDCs recruit dysfunctional CD161+CD8+ T cells, activating TNFR2 signaling to promote mregDC differentiation.
• Found that dual blockade of TNFR2 and PD-L1 significantly reduced tumor burden in mregDC-rich HCC models.
• Observed interactions between mregDCs and FCN1+ monocytes, a myeloid-derived suppressor cell (MDSC)-like population.

Conclusions:

• Characterized an mregDC-mediated immunosuppressive network in relapse HCC.
• Nominated TNFR2 as a potential therapeutic target for myeloid-focused HCC immunotherapy.