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.

大多数肝细胞癌（hepatocellular carcinoma, HCC）患者对免疫检查点抑制剂（immune checkpoint inhibitors, ICI）的治疗应答仍不甚理想，亟需发掘可用于药物靶向及患者筛选的功能性生物标志物，以提升免疫检查点抑制剂的治疗效果。本研究报道，Wnt/β-连环蛋白信号通路（Wnt/β-catenin signaling）的关键辅因子BCL9可作为抗PD-(L)1治疗（anti-PD-(L)1 therapy）的新型生物标志物。结构创新性BCL9抑制剂hsBCL9Z96具备强劲的肿瘤穿透能力，将其与抗PD-L1联合使用时，在多种临床前模型中，其治疗响应显著优于当前肝细胞癌一线免疫治疗方案——抗PD-L1联合抗血管内皮生长因子（anti-VEGF）疗法。机制层面，BCL9抑制可通过抑制骨形态发生蛋白4（BMP4）的分泌，将促肿瘤巨噬细胞重编程为抑肿瘤表型，并通过下调肿瘤细胞表面CD24的表达促进吞噬作用，进而通过重新激活巨噬细胞介导的抗原呈递，实现T细胞的复苏活化。上述研究结果不仅拓展了我们对肿瘤来源的Wnt/β-连环蛋白信号通路如何调控肿瘤微环境（tumor microenvironment）中先天免疫系统（innate immune system）与适应性免疫应答（adaptive immune response）的认知，同时也为通过hsBCL9Z96靶向BCL9以增强抗PD-L1治疗效果提供了极具前景的联合治疗策略。