Daman Andrew W, Antonelli Anthony C, Redelman-Sidi Gil, Paddock Lucinda, Khayat Shireen, Ketavarapu Mythili, Cheong Jin Gyu, Jurado Leonardo F, Benjamin Anna, Jiang Song, Ahimovic Dughan, Lawless Victoria R, Bale Michael J, Loutochin Oleg, McPherson Victor A, Divangahi Maziar, Niec Rachel E, Pe'er Dana, Pietzak Eugene, Josefowicz Steven Z, Glickman Michael S
Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA; Department of Pathology and Laboratory Medicine, Division of Cell and Cancer Pathobiology, Weill Cornell Medicine, New York, NY, USA.
Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA; Immunology Program, Sloan Kettering Institute, New York, NY, USA.
Cancer Cell. 2025 May 28. doi: 10.1016/j.ccell.2025.05.002.
Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder colonizes the bone marrow and, in both mice and humans, reprograms HSPCs to alter and amplify myelopoiesis. BCG-reprogrammed HSPCs are sufficient to confer augmented anti-tumor immunity through production of neutrophils, monocytes, and dendritic cells that broadly remodel the tumor microenvironment, drive T cell-dependent anti-tumor responses, and synergize with checkpoint blockade. We conclude that bladder BCG acts systemically through hematopoiesis, highlighting the broad potential of HSPC reprogramming to enhance the innate drivers of T cell-dependent tumor immunity.
牛分枝杆菌卡介苗（BCG）是一种抗结核疫苗，也是一种膀胱癌免疫疗法。静脉注射BCG时，它会对骨髓造血干细胞和祖细胞（HSPCs）进行重编程，从而产生针对感染的异源保护作用。HSPC重编程是否有助于膀胱内注射BCG的抗肿瘤作用尚不清楚。我们证明，膀胱内注射的BCG会定殖于骨髓，并且在小鼠和人类中，都会对HSPCs进行重编程，以改变和增强骨髓生成。经BCG重编程的HSPCs足以通过产生中性粒细胞、单核细胞和树突状细胞来增强抗肿瘤免疫力，这些细胞可广泛重塑肿瘤微环境、驱动T细胞依赖性抗肿瘤反应并与检查点阻断协同作用。我们得出结论，膀胱BCG通过造血作用发挥全身作用，突出了HSPC重编程在增强T细胞依赖性肿瘤免疫的先天驱动因素方面的广泛潜力。
