Dataset supporting "Targeting tumor-intrinsic BCL9 reverses the resistance to immunotherapy by eliciting macrophage-mediated phagocytosis and antigen presentation"

Response to immune checkpoint inhibitors (ICI) remains unsatisfactory in most patients with hepatocellular carcinoma (HCC). It is urgent to seek functional biomarkers for pharmacological targeting and patient selection to improve ICI efficacy. Here, we reported BCL9, a critical co-factor for Wnt/β-catenin signaling, as a novel biomarker for anti-PD-(L)1 therapy. A structurally innovative peptide BCL9 inhibitor hsBCL9Z96 showed robust tumor-penetrating capacity and the combination of hsBCL9Z96 with anti-PD-L1 surprisingly produced superior therapeutic response compared with anti-PD-L1 + anti-VEGF combination, the current first-line immunotherapy for HCC, in multiple preclinical models. Mechanistically, BCL9 inhibition educated tumor-promoting macrophages to a tumor suppressive phenotype through inhibiting BMP4 secretion and promoted phagocytosis by downregulating the tumoral CD24, thereby resulting in rejuvenation of T cells through re-triggered macrophage-mediated antigen presentation. These data not only extend our understanding of how tumor-derived Wnt/β-catenin signaling orchestrates innate immune system and adaptive immune response in the tumor microenvironment but also provide novel evidence that pharmacological targeting BCL9 with hsBCL9Z96 is a promising combination strategy to boost anti-PD-L1 efficacy.