Julia Frede,Julia C Poller,Kayleen Shi,Hannah Stuart,Noori Sotudeh,Claire Havig,Klothilda Lim,Caroline R M Wiggers,Eugene Y Cho,Tushara Vijaykumar,Jianlin Liu,Johannes M Waldschmidt,Monica S Nair,Praveen Anand,Valeriya Dimitrova,Anna Montanaro,Andrew J Yee,Nikhil C Munshi,Kenneth C Anderson,Nathan Martin,Shari M Kaiser,Marc-Steffen Raab,Noopur S Raje,Birgit Knoechel,Jens G Lohr
{"title":"CAR-T细胞疗法重塑了内源性T细胞景观,并预测了多发性骨髓瘤的治疗反应。","authors":"Julia Frede,Julia C Poller,Kayleen Shi,Hannah Stuart,Noori Sotudeh,Claire Havig,Klothilda Lim,Caroline R M Wiggers,Eugene Y Cho,Tushara Vijaykumar,Jianlin Liu,Johannes M Waldschmidt,Monica S Nair,Praveen Anand,Valeriya Dimitrova,Anna Montanaro,Andrew J Yee,Nikhil C Munshi,Kenneth C Anderson,Nathan Martin,Shari M Kaiser,Marc-Steffen Raab,Noopur S Raje,Birgit Knoechel,Jens G Lohr","doi":"10.1038/s41375-025-02766-5","DOIUrl":null,"url":null,"abstract":"While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8 + T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the 'mileage' of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"54 1","pages":""},"PeriodicalIF":13.4000,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.\",\"authors\":\"Julia Frede,Julia C Poller,Kayleen Shi,Hannah Stuart,Noori Sotudeh,Claire Havig,Klothilda Lim,Caroline R M Wiggers,Eugene Y Cho,Tushara Vijaykumar,Jianlin Liu,Johannes M Waldschmidt,Monica S Nair,Praveen Anand,Valeriya Dimitrova,Anna Montanaro,Andrew J Yee,Nikhil C Munshi,Kenneth C Anderson,Nathan Martin,Shari M Kaiser,Marc-Steffen Raab,Noopur S Raje,Birgit Knoechel,Jens G Lohr\",\"doi\":\"10.1038/s41375-025-02766-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. 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The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.
While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8 + T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the 'mileage' of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues