Jurado Leonardo F, Daman Andrew W, Li Ziyi, Ross Vanessa M S, Nikolaou Kristina, Tran Kim A, Loutochin Oleg, McPherson Victor A, Prével Renaud, Tarancón Raquel, Couto Katalina, Pernet Erwan, Khan Nargis, Cheong Jin-Gyu, Ramaiah Reshma, Ketavarapu Mythili, Kaufmann Eva, Glickman Michael S, Thanabalasuriar Ajitha, Josefowicz Steven Z, Divangahi Maziar
Department of Pathology, Department of Microbiology & Immunology, Department of Medicine, McGill International TB Centre, Meakins-Christie Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
Department of Pathology and Laboratory Medicine, Division of Cell and Cancer Biology, and Immunology & Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA.
Immunity. 2025 Aug 12;58(8):1984-2001.e6. doi: 10.1016/j.immuni.2025.05.026. Epub 2025 Jun 23.
In patients with non-muscle invasive bladder cancer, the standard immunotherapy involves intravesical Bacillus Calmette-Guérin (BCG). However, its success requires repeated doses, and ∼50% of patients do not benefit. Using a preclinical orthotopic bladder cancer model, we found that a single intravesical dose of combined BCG and β-glucan immunotherapy eradicated aggressive tumors, resulting in 100% survival. Through single-cell transcriptomic/epigenomic analysis, flow cytometry, and intravital imaging, we show that BCG and β-glucan reprogrammed hematopoietic stem and progenitor cells with imprinting in innate immune cells, particularly neutrophils. Reprogrammed neutrophils exhibited increased reactive oxygen species (ROS) production and infiltration into the tumor core, reducing tumor vascularization and growth. The tumor microenvironment can convert neutrophils into protumor cells; BCG and β-glucan prevented this conversion, promoting sustained antitumoral activity. These findings support β-glucan as a safe, effective adjuvant to enhance BCG immunotherapy in bladder cancer and other solid tumors.
在非肌肉浸润性膀胱癌患者中，标准免疫疗法包括膀胱内灌注卡介苗（BCG）。然而，其成功需要重复给药，且约50%的患者并无获益。利用临床前原位膀胱癌模型，我们发现单次膀胱内灌注联合BCG和β-葡聚糖免疫疗法可根除侵袭性肿瘤，实现100%的生存率。通过单细胞转录组学/表观基因组分析、流式细胞术和活体成像，我们发现BCG和β-葡聚糖对造血干细胞和祖细胞进行了重编程，并在先天免疫细胞（尤其是中性粒细胞）中留下印记。重编程后的中性粒细胞表现出活性氧（ROS）生成增加，并浸润到肿瘤核心，减少肿瘤血管生成和生长。肿瘤微环境可将中性粒细胞转化为促肿瘤细胞；BCG和β-葡聚糖可防止这种转化，促进持续的抗肿瘤活性。这些发现支持β-葡聚糖作为一种安全、有效的佐剂，可增强BCG在膀胱癌和其他实体瘤中的免疫治疗效果。
