Hualin Chen, Zhaoheng Jin, Yueqiang Peng, Yingjie Li, Ziyi Li, Xuebin Zhang, Yi Xie, Jie Dong, Lin Ma, Zhigang Ji
{"title":"MYBL2hi肿瘤干细胞与SPP1+巨噬细胞的恶性联合使膀胱癌对新辅助免疫治疗产生耐药性。","authors":"Hualin Chen, Zhaoheng Jin, Yueqiang Peng, Yingjie Li, Ziyi Li, Xuebin Zhang, Yi Xie, Jie Dong, Lin Ma, Zhigang Ji","doi":"10.1136/jitc-2024-011319","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant immune checkpoint blockade (nICB) has revolutionized cancer treatment, yet the underlying mechanisms of resistance in bladder cancer remain to be explored.</p><p><strong>Methods: </strong>We conducted single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells, tumor tissues, adjacent normal tissues, and metastatic lymph nodes from 2 nICB-naïve and 10 nICB-treated patients with bladder cancer (5 responders and 5 non-responders). Spatial RNA sequencing was performed on tumor slides from two responders and four non-responders. Findings were validated by multiplex immunohistochemistry, mice orthotopic bladder cancer model, and flow cytometry assays.</p><p><strong>Results: </strong>nICB remodeled the tumor microenvironment of bladder cancer from both single-cell and spatial perspectives. scRNA-seq analysis revealed a significant increase in MYBL2<sup>hi</sup> cancer stem cells (CSCs) among non-responders. Analysis of the myeloid population showed that SPP1+ macrophages associated with angiogenesis were linked to CD8+ T cell exclusion. Further investigation into cell-cell communication revealed a propensity for bidirectional crosstalk between MYBL2<sup>hi</sup> CSCs and SPP1+ macrophages in non-responders. MYBL2<sup>hi</sup> CSCs derived CCL15, which bound to CCR1 and induced SPP1 upregulation in macrophages which reciprocally enhanced bladder cancer stemness and resistance to nICB through the SPP1-ITGα9β1 axis. Additionally, we identified an aged CCL3+ neutrophil population that interacted with SPP1+ macrophages through a positive feedback loop, contributing to nICB resistance. Finally, in vivo studies demonstrated that combined MYBL2 knockdown and SPP1 targeting synergistically enhanced ICB efficacy in bladder cancer.</p><p><strong>Conclusions: </strong>Our research reveals transcriptomic characteristics associated with distinct therapeutic responses to nICB treatment, offering a foundation for optimizing personalized neoadjuvant strategies in bladder cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3000,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258365/pdf/","citationCount":"0","resultStr":"{\"title\":\"Malevolent alliance of MYBL2<sup>hi</sup> cancer stem cell and SPP1+ macrophage confers resistance to neoadjuvant immunotherapy in bladder cancer.\",\"authors\":\"Hualin Chen, Zhaoheng Jin, Yueqiang Peng, Yingjie Li, Ziyi Li, Xuebin Zhang, Yi Xie, Jie Dong, Lin Ma, Zhigang Ji\",\"doi\":\"10.1136/jitc-2024-011319\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Neoadjuvant immune checkpoint blockade (nICB) has revolutionized cancer treatment, yet the underlying mechanisms of resistance in bladder cancer remain to be explored.</p><p><strong>Methods: </strong>We conducted single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells, tumor tissues, adjacent normal tissues, and metastatic lymph nodes from 2 nICB-naïve and 10 nICB-treated patients with bladder cancer (5 responders and 5 non-responders). Spatial RNA sequencing was performed on tumor slides from two responders and four non-responders. Findings were validated by multiplex immunohistochemistry, mice orthotopic bladder cancer model, and flow cytometry assays.</p><p><strong>Results: </strong>nICB remodeled the tumor microenvironment of bladder cancer from both single-cell and spatial perspectives. scRNA-seq analysis revealed a significant increase in MYBL2<sup>hi</sup> cancer stem cells (CSCs) among non-responders. Analysis of the myeloid population showed that SPP1+ macrophages associated with angiogenesis were linked to CD8+ T cell exclusion. Further investigation into cell-cell communication revealed a propensity for bidirectional crosstalk between MYBL2<sup>hi</sup> CSCs and SPP1+ macrophages in non-responders. MYBL2<sup>hi</sup> CSCs derived CCL15, which bound to CCR1 and induced SPP1 upregulation in macrophages which reciprocally enhanced bladder cancer stemness and resistance to nICB through the SPP1-ITGα9β1 axis. Additionally, we identified an aged CCL3+ neutrophil population that interacted with SPP1+ macrophages through a positive feedback loop, contributing to nICB resistance. Finally, in vivo studies demonstrated that combined MYBL2 knockdown and SPP1 targeting synergistically enhanced ICB efficacy in bladder cancer.</p><p><strong>Conclusions: </strong>Our research reveals transcriptomic characteristics associated with distinct therapeutic responses to nICB treatment, offering a foundation for optimizing personalized neoadjuvant strategies in bladder cancer.</p>\",\"PeriodicalId\":14820,\"journal\":{\"name\":\"Journal for Immunotherapy of Cancer\",\"volume\":\"13 7\",\"pages\":\"\"},\"PeriodicalIF\":10.3000,\"publicationDate\":\"2025-07-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258365/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal for Immunotherapy of Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/jitc-2024-011319\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal for Immunotherapy of Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jitc-2024-011319","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Malevolent alliance of MYBL2hi cancer stem cell and SPP1+ macrophage confers resistance to neoadjuvant immunotherapy in bladder cancer.
Background: Neoadjuvant immune checkpoint blockade (nICB) has revolutionized cancer treatment, yet the underlying mechanisms of resistance in bladder cancer remain to be explored.
Methods: We conducted single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells, tumor tissues, adjacent normal tissues, and metastatic lymph nodes from 2 nICB-naïve and 10 nICB-treated patients with bladder cancer (5 responders and 5 non-responders). Spatial RNA sequencing was performed on tumor slides from two responders and four non-responders. Findings were validated by multiplex immunohistochemistry, mice orthotopic bladder cancer model, and flow cytometry assays.
Results: nICB remodeled the tumor microenvironment of bladder cancer from both single-cell and spatial perspectives. scRNA-seq analysis revealed a significant increase in MYBL2hi cancer stem cells (CSCs) among non-responders. Analysis of the myeloid population showed that SPP1+ macrophages associated with angiogenesis were linked to CD8+ T cell exclusion. Further investigation into cell-cell communication revealed a propensity for bidirectional crosstalk between MYBL2hi CSCs and SPP1+ macrophages in non-responders. MYBL2hi CSCs derived CCL15, which bound to CCR1 and induced SPP1 upregulation in macrophages which reciprocally enhanced bladder cancer stemness and resistance to nICB through the SPP1-ITGα9β1 axis. Additionally, we identified an aged CCL3+ neutrophil population that interacted with SPP1+ macrophages through a positive feedback loop, contributing to nICB resistance. Finally, in vivo studies demonstrated that combined MYBL2 knockdown and SPP1 targeting synergistically enhanced ICB efficacy in bladder cancer.
Conclusions: Our research reveals transcriptomic characteristics associated with distinct therapeutic responses to nICB treatment, offering a foundation for optimizing personalized neoadjuvant strategies in bladder cancer.
期刊介绍：
The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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