Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-05-29 DOI:10.1016/j.ccell.2025.05.002

Andrew W. Daman, Anthony C. Antonelli, Gil Redelman-Sidi, Lucinda Paddock, Shireen Khayat, Mythili Ketavarapu, Jin Gyu Cheong, Leonardo F. Jurado, Anna Benjamin, Song Jiang, Dughan Ahimovic, Victoria R. Lawless, Michael J. Bale, Oleg Loutochin, Victor A. McPherson, Maziar Divangahi, Rachel E. Niec, Dana Pe’er, Eugene Pietzak, Steven Z. Josefowicz, Michael S. Glickman

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Abstract

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.

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微生物癌症免疫疗法重新编程造血以增强髓细胞驱动的抗肿瘤免疫

牛分枝杆菌卡介苗（BCG）是一种结核病疫苗和膀胱癌的免疫疗法。当静脉给药时，卡介苗重新编程骨髓造血干细胞和祖细胞（HSPCs），导致对感染的异源保护。HSPC重编程是否有助于膀胱注射卡介苗的抗肿瘤作用尚不清楚。我们证明，在膀胱中施用卡介苗定殖骨髓，并在小鼠和人类中重新编程HSPCs以改变和扩增骨髓生成。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，这些细胞广泛地重塑肿瘤微环境，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通过造血系统起作用，突出了HSPC重编程增强T细胞依赖性肿瘤免疫先天驱动的广泛潜力。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.