Effect of cDC2 licensing by CCL5 ⁺ Th1 cells following BCL9/BCL9L inhibition on CD8 ⁺ T cell cross-priming for enhanced anti-tumor responses.

Abstract

e16255 Background: Hepatocellular carcinoma (HCC) exhibits limited response to immune checkpoint blockade (ICB) therapy, highlighting the need to further elucidate the immune characteristics of the tumor microenvironment (TME). While most previous studies have focused on cDC1 cells, cDC2 cells—despite their abundance in HCC tumors—have often been overlooked. Recent observations indicate that in patients who respond favorably to ICB therapy, cDC2 displays enhanced antigen cross-presentation signals, suggesting a unique role for cDC2 in HCC immune responses. Methods: We systematically analyzed the distribution and function of dendritic cell (DC) subsets in tumor tissues and peripheral blood of HCC patients, with an emphasis on the role of cDC2 in antigen translocation, processing, and presentation. By integrating immunohistochemistry, flow cytometry, and single-cell transcriptomic data, we evaluated the interactions between cDC2 and various T-cell subpopulations. We further investigated how inhibition of the Wnt/β-catenin pathway via BCL9/BCL9L blockade affects cDC2 and T-cell subsets, and explored the mechanism by which circRNA-encoded cryptic antigens activate cDC2. Results: Our findings show that cDC2-mediated antigen cross-presentation depends on the presence of CD4⁺ T cells rather than CD8⁺ T cells. We identified a highly differentiated CCL5⁺ Th1 subset within the TME that produces robust levels of IFNγ. This subset interacts with cDC2 to enhance antigen uptake and presentation. Moreover, we show that inhibiting the Wnt/β-catenin signaling pathway through BCL9/BCL9L blockade promotes the generation of CCL5 + Th1 cells. These cells then interact with cDC2 through the IFNγ/TIM4 signaling axis, resulting in enhanced antigen uptake and presentation by cDC2.Furthermore, we found that circRNA-encoded cryptic antigens can be recognized and presented by cDC2, thereby eliciting a potent anti-tumor immune response. Conclusions: Our results indicate that boosting cDC2 activity could be a promising approach to enhance the effectiveness of ICB therapy, especially in tumors with limited cDC1 presence. This study offers fresh perspectives on the immune composition of HCC and highlights potential therapeutic strategies aimed at modulating the TME.