Cancer immunology research最新文献_第6页

Spatiotemporal immune landscape and long-term immune memory in POLE-mutant endometrial cancer at the single-cell level. 在单细胞水平上pole突变子宫内膜癌的时空免疫景观和长期免疫记忆。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-29 DOI: 10.1158/2326-6066.CIR-25-0083

Koen Brummel, Marta Requesens, Nienke van Rooij, Hagma H Workel, Florine A Eggink, Annechien Plat, René Wardenaar, Diana C J Spierings, Floris Foijer, David N Church, Joost Bart, Hans W Nijman, Marco de Bruyn

{"title":"Spatiotemporal immune landscape and long-term immune memory in POLE-mutant endometrial cancer at the single-cell level.","authors":"Koen Brummel, Marta Requesens, Nienke van Rooij, Hagma H Workel, Florine A Eggink, Annechien Plat, René Wardenaar, Diana C J Spierings, Floris Foijer, David N Church, Joost Bart, Hans W Nijman, Marco de Bruyn","doi":"10.1158/2326-6066.CIR-25-0083","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0083","url":null,"abstract":"Polymerase epsilon mutant (POLE-mut) endometrial cancers (EC) are characterized by a near 100% disease-specific survival rate, even when treated by surgery alone. This spectacular survival, combined with the ultramutated genome and high level of neoantigens in these tumors, indicates a substantial degree of immune control in preventing disease spread and recurrence. Although these features are intriguing, the immune infiltration of POLE-mut EC has predominantly been confined to immunohistochemistry studies. Here, we used state of the art single-cell RNA and TCR sequencing to characterize the immune landscape of POLE-mutant ECs. Moreover, we uniquely analyzed patient blood samples taken two to eight years after curative treatment to assess formation of long-term immune memory in circulation. We identified specialized tumor-infiltrating myeloid subsets at different stages of maturation, an array of lymphocytes ranging from immature to cytotoxic and adaptive natural killer (NK) as well as tumor-reactive exhausted and effector T cells, contributing to a highly inflammatory anti-tumor response. Remarkably, our analysis of blood samples taken years after curative treatment uncovered the presence of tumor-reactive T cell clones that matched the primary tumor. This indicates the formation of systemic long-term memory immune responses in POLE-mut EC survivors. Our study highlights the distinctive immunogenicity of POLE-mut EC and identifies key features associated with persistent anti-tumor immunity that may contribute to prolonged, relapse-free survival.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Myeloid Cells for Cancer Immunotherapy. 靶向骨髓细胞用于癌症免疫治疗。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-28 DOI: 10.1158/2326-6066.CIR-25-0159

Lucas Blanchard, Andrew Mijacika, Juan C Osorio

{"title":"Targeting Myeloid Cells for Cancer Immunotherapy.","authors":"Lucas Blanchard, Andrew Mijacika, Juan C Osorio","doi":"10.1158/2326-6066.CIR-25-0159","DOIUrl":"10.1158/2326-6066.CIR-25-0159","url":null,"abstract":"Myeloid cells - including monocytes, macrophages, dendritic cells, and granulocytes - are critical architects of the tumor microenvironment, where they exert diverse functions ranging from immunosuppressive to immunostimulatory. Advances in single-cell omics and high-dimensional immune profiling have unveiled the remarkable heterogeneity and plasticity of these cells, revealing lineage-specialized functions that shape cancer immunity. These discoveries have sparked growing interest in therapeutically targeting myeloid cells as a next generation strategy in cancer immunotherapy. As a complementary or alternative approach to T cell-centered immunotherapies, myeloid-directed therapies offer unique opportunities to reprogram the immune landscape, enhance antitumor responses, and overcome resistance mechanisms. In this review, we highlight recent discoveries in myeloid cell biology in cancer and discuss emerging therapeutic targets, with an emphasis on antibody-based therapies that have reached clinical development. We further provide perspective on translational challenges to implement these approaches into the clinic, and discuss how Fc-engineering and rational antibody design can optimize myeloid cell engagement and amplify their immune effector functions. Together, these advances position myeloid-directed immunotherapies as a promising approach to enhance the efficacy and durability of cancer treatment.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sintilimab plus anlotinib in patients with pre-treated locally advanced or metastatic sarcoma: a prospective, single-arm, phase II clinical trial. sintilmab联合anlotinib治疗局部晚期或转移性肉瘤：一项前瞻性单组II期临床试验

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-28 DOI: 10.1158/2326-6066.CIR-25-0491

Heng Fu, Zengjun Liu, Mengyao Liu, Jing Xu, Xin Xu, Ting Hao, Guiying Wei, Hongtu Yuan, Jianbo Zhang, Dongyuan Zhu

{"title":"Sintilimab plus anlotinib in patients with pre-treated locally advanced or metastatic sarcoma: a prospective, single-arm, phase II clinical trial.","authors":"Heng Fu, Zengjun Liu, Mengyao Liu, Jing Xu, Xin Xu, Ting Hao, Guiying Wei, Hongtu Yuan, Jianbo Zhang, Dongyuan Zhu","doi":"10.1158/2326-6066.CIR-25-0491","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0491","url":null,"abstract":"Advanced sarcomas have limited treatment options after standard therapy, and therefore we investigated the efficacy and safety of sintilimab plus anlotinib in this setting. Patients aged 18-75 years with advanced sarcomas and prior systemic therapy were enrolled. Patients with untreated, primary chemotherapy-resistant tumor types, such as alveolar soft part sarcoma, clear cell sarcoma, etc., were alsoincluded. Patients received sintilimab 200 mg (d1) and anlotinib (8, 10, or 12 mg investigator-chosen, d1-14), every 3 weeks. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). The predictive value of tertiary lymphoid structure (TLS) was explored. A total of 42 patients were enrolled and 40 (95.2%) patients were non-ASPS. The ORR and DCR was 30.9% (95% CI, 16.4-45.5%) and 76.2% (95% CI, 62.8-89.6%), respectively, with a median follow-up duration of 15.4 months, the median PFS was 5.0 months (95% CI, 2.8-10.2). The median OS was not reached. The most common AEs included elevated lactate dehydrogenase (28.57%), hypoproteinemia (21.43%), and increased thyroid stimulating hormone (21.43%). The most common ≥ grade 3 AEs were hypertension (4.76%) and hyponatremia (4.76%). Two serious AEs (one hepatitis and one intestinal perforation) were recorded. The ORR in TLS-positive patients (n = 7) was significantly higher than that in TLS-negative patients (n = 28) (71.4% vs. 25.0%, P = 0.033). Therefore, sintilimab plus anlotinib demonstrated promising antitumor activity with manageable toxicity in advanced sarcomas, particularly among TLS-positive patients.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IFNγ-induced PD-L1+MHC II+ macrophages and Tim-3+ tumor-reactive CD8+ T cells predict a response to anti-PD-1 therapy in tumor-bearing mice. ifn γ诱导的PD-L1+MHC II+巨噬细胞和Tim-3+肿瘤反应性CD8+ T细胞预测了荷瘤小鼠对抗pd -1治疗的反应。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-28 DOI: 10.1158/2326-6066.CIR-24-0835

Jelena Gabrilo, Sylvie Vande Velde, Coralie Henin, Sébastien Denanglaire, Abdulkader Azouz, Louis Boon, Benoit J Van den Eynde, Muriel Moser, Stanislas Goriely, Oberdan Leo

{"title":"IFNγ-induced PD-L1+MHC II+ macrophages and Tim-3+ tumor-reactive CD8+ T cells predict a response to anti-PD-1 therapy in tumor-bearing mice.","authors":"Jelena Gabrilo, Sylvie Vande Velde, Coralie Henin, Sébastien Denanglaire, Abdulkader Azouz, Louis Boon, Benoit J Van den Eynde, Muriel Moser, Stanislas Goriely, Oberdan Leo","doi":"10.1158/2326-6066.CIR-24-0835","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0835","url":null,"abstract":"While immune checkpoint inhibitors have led to durable responses in various cancer types, a substantial proportion of patients do not respond to these interventions. To uncover potential factors associated with a positive response to immunotherapy, we used a bilateral tumor model using P815 mastocytoma implanted in DBA/2 mice. In this model, only a fraction of tumor-bearing mice responds to anti-PD-1 treatment. Thus, it provides a valuable model to explore the influence of the tumor microenvironment (TME) in determining the efficacy of immune checkpoint blockade (ICB)-based immunotherapies. It also allows for the analysis of a pretreatment tumor and inference of its treatment outcome based on the response observed in the contralateral tumor. Herein, we report that tumor-reactive CD8+ T-cell clones expressing high levels of Tim-3 were associated with a positive antitumor response following anti-PD-1 administration. Our study also revealed distinct differentiation dynamics in tumor-infiltrating myeloid cells in responding and non-responding mice. An IFNγ-enriched TME promoted the differentiation of monocytes into PD-L1posMHC IIhigh cells in mice responding to immunotherapy. Monocytes present in the TME of non-responding mice failed to reach the same final stage of differentiation trajectory, suggesting that an altered monocyte to macrophage differentiation route may hamper the response to ICB. These insights will direct future research towards a temporal analysis of tumor-associated macrophages (TAMs), aiming to identify factors responsible for transitions between differentiation states within the TME. This approach may pave the way to novel strategies to enhance the efficacy of PD-1 blockade.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of proton minibeam radiation therapy on anti-tumor immune responses in a rat model of glioblastoma. 质子微束放射治疗对胶质母细胞瘤模型大鼠抗肿瘤免疫反应的评价。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-20 DOI: 10.1158/2326-6066.CIR-24-0902

Lorea Iturri, Miriam Riquelme-Perez, Pierre-Emmanuel Bonté, Sarah Potiron, Christel Goudot, Marjorie Juchaux, Elise Brisebard, Cristèle Gilbert, Julie Espenon, Ramón Ortiz, Annalisa Patriarca, Ludovic De Marzi, Sebastián Amigorena, Yolanda Prezado

{"title":"Evaluation of proton minibeam radiation therapy on anti-tumor immune responses in a rat model of glioblastoma.","authors":"Lorea Iturri, Miriam Riquelme-Perez, Pierre-Emmanuel Bonté, Sarah Potiron, Christel Goudot, Marjorie Juchaux, Elise Brisebard, Cristèle Gilbert, Julie Espenon, Ramón Ortiz, Annalisa Patriarca, Ludovic De Marzi, Sebastián Amigorena, Yolanda Prezado","doi":"10.1158/2326-6066.CIR-24-0902","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0902","url":null,"abstract":"Treating radioresistant tumors like glioblastoma multiforme (GBM) remains a challenge exacerbated by their immunosuppressive nature. Radiation therapy has an immunomodulatory role, both immunosuppressive and immunostimulatory. The nature of the effects depends on the total dose, dose per fraction, dose delivery method and treatment length. Hypofractionation is observed to tip the balance towards immune stimulation. However, the use of hypofractionation is restricted in bulky tumours, i.e. gliomas, due to the high risk of toxicity. Therefore, finding new strategies leading to more favourable immune responses while reducing normal tissue toxicities could improve cancer treatment. Here we examine anti-tumoral immune responses to proton minibeam radiation therapy (pMBRT). However, its immunomodulatory effects are not fully understood. To explore this, we conducted an in-depth characterization of the immune response to a curative dose of pMBRT in a preclinical orthotopic rat model of glioblastoma. Our findings revealed a close association between pMBRT and the immune response. pMBRT increased lymphocyte density in tumors more effectively than conventional proton therapy. Single-cell transcriptomics identified several immune cell types and unique transcriptional changes in tumor immune cells post-pMBRT, including increased antibody production, chemotactic cytokine expression, and interferon responses. These results underscore the critical role of adaptive immunity, specifically T cells, in pMBRT's mechanism. The potential of pMBRT to trigger an anti-tumor immune response in a single radiotherapy session with minimal damage to healthy tissue makes it a promising candidate for future clinical trials and radio-immunotherapy combinations.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tissue-specific immunosuppressive and proliferating macrophages fuel early metastatic progression of human colorectal cancer to liver. 组织特异性免疫抑制和增殖巨噬细胞促进人类结直肠癌向肝脏的早期转移进展。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-19 DOI: 10.1158/2326-6066.CIR-25-0031

Paolo Marzano, Cristiana Soldani, Valentina Cazzetta, Barbara Franceschini, Sara Terzoli, Anna Carletti, Michela Anna Polidoro, Federica Marchesi, Massimo Locati, Gianluca Basso, Ana Lleo, Guido Costa, Guido Torzilli, Flavio Milana, Rocco Piazza, Paola Spaggiari, Luca Di Tommaso, Joanna Mikulak, Domenico Mavilio, Matteo Donadon

{"title":"Tissue-specific immunosuppressive and proliferating macrophages fuel early metastatic progression of human colorectal cancer to liver.","authors":"Paolo Marzano, Cristiana Soldani, Valentina Cazzetta, Barbara Franceschini, Sara Terzoli, Anna Carletti, Michela Anna Polidoro, Federica Marchesi, Massimo Locati, Gianluca Basso, Ana Lleo, Guido Costa, Guido Torzilli, Flavio Milana, Rocco Piazza, Paola Spaggiari, Luca Di Tommaso, Joanna Mikulak, Domenico Mavilio, Matteo Donadon","doi":"10.1158/2326-6066.CIR-25-0031","DOIUrl":"10.1158/2326-6066.CIR-25-0031","url":null,"abstract":"Early synchronous colorectal liver metastasis (CRLM) represents a clinical condition characterized by the simultaneous presence of primary colorectal cancer (CRC) and metastatic liver lesions. In this study, we characterized the tissue-specific transcriptomes, phenotypes, and functional relevance of tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) of CRC and CRLM specimens from patients who underwent simultaneous surgical removal of these malignancies. The high-throughput single-cell transcriptional analysis revealed an inverse ratio of inflammatory and immunoregulatory TAMs in the CRC and CRLM TMEs, along with heterogeneity in both tumoral tissues. Further, we found that inflammatory TAMs in CRC expressed inhibitory ligands that might support immune escape, thus favoring liver metastatic progression. In contrast, CRLM lesions possessed a highly immunosuppressive milieu characterized by large proliferative CTLA4+ immunoregulatory TAMs and by the presence of IL7R+ cytotoxic TAMs. Higher frequencies of these specific TAM subsets in CRLM were associated with shorter disease-free survival and worse patient prognosis. The identification and characterization of immunoregulatory TAMs preferentially enriched in CRLM is key for the development of novel immunotherapeutic strategies aimed at boosting anticancer immune responses within TME.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neoadjuvant immunotherapy promotes the formation of mature tertiary lymphoid structures in a remodeled pancreatic tumor microenvironment. 在重建的胰腺肿瘤微环境中，新辅助免疫治疗促进成熟三级淋巴结构的形成。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-15 DOI: 10.1158/2326-6066.CIR-25-0387

Dimitrios N Sidiropoulos, Sarah M Shin, Meredith Wetzel, Alexander A Girgis, Daniel Bergman, Ludmila Danilova, Susheel Perikala, Daniel Shu, Janelle M Montagne, Atul Deshpande, James Leatherman, Lucie Dequiedt, Victoria Jacobs, Aleksandra Ogurtsova, Guanglan Mo, Xuan Yuan, Dmitrijs Lvovs, Genevieve Stein-O'Brien, Mark Yarchoan, Qingfeng Zhu, Elizabeth I Harper, Ashani T Weeraratna, Ashley L Kiemen, Elizabeth M Jaffee, Lei Zheng, Won Jin Ho, Robert A Anders, Elana J Fertig, Luciane T Kagohara

{"title":"Neoadjuvant immunotherapy promotes the formation of mature tertiary lymphoid structures in a remodeled pancreatic tumor microenvironment.","authors":"Dimitrios N Sidiropoulos, Sarah M Shin, Meredith Wetzel, Alexander A Girgis, Daniel Bergman, Ludmila Danilova, Susheel Perikala, Daniel Shu, Janelle M Montagne, Atul Deshpande, James Leatherman, Lucie Dequiedt, Victoria Jacobs, Aleksandra Ogurtsova, Guanglan Mo, Xuan Yuan, Dmitrijs Lvovs, Genevieve Stein-O'Brien, Mark Yarchoan, Qingfeng Zhu, Elizabeth I Harper, Ashani T Weeraratna, Ashley L Kiemen, Elizabeth M Jaffee, Lei Zheng, Won Jin Ho, Robert A Anders, Elana J Fertig, Luciane T Kagohara","doi":"10.1158/2326-6066.CIR-25-0387","DOIUrl":"10.1158/2326-6066.CIR-25-0387","url":null,"abstract":"Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Herein, we report the generation of a spatial multi-omics atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning across distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that significantly associated with improved survival in PDAC patients. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

USP15 Facilitates Colorectal Cancer Immune Evasion through SMYD3/CCL2-Dependent Myeloid-Derived Suppressor Cell Recruitment. USP15通过SMYD3/ ccl2依赖的髓源性抑制细胞募集促进结直肠癌免疫逃避。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-01 DOI: 10.1158/2326-6066.CIR-24-1194

Shuling Han, Luying Cui, Bojun Wang, Yuli Ruan, Mengde Shi, Chang Hong, Xin Guan, Zhuo Chen, Yingjue Li, Yuanyu Liao, Ming Ma, Xiaolin Lu, Hong Wang, Yanqiao Zhang, Chao Liu

{"title":"USP15 Facilitates Colorectal Cancer Immune Evasion through SMYD3/CCL2-Dependent Myeloid-Derived Suppressor Cell Recruitment.","authors":"Shuling Han, Luying Cui, Bojun Wang, Yuli Ruan, Mengde Shi, Chang Hong, Xin Guan, Zhuo Chen, Yingjue Li, Yuanyu Liao, Ming Ma, Xiaolin Lu, Hong Wang, Yanqiao Zhang, Chao Liu","doi":"10.1158/2326-6066.CIR-24-1194","DOIUrl":"10.1158/2326-6066.CIR-24-1194","url":null,"abstract":"Colorectal cancer creates a suppressive tumor immune microenvironment that leads to tumor progression and resistance to immune checkpoint inhibitor therapy. Ubiquitin-specific protease 15 (USP15) broadly regulates immune responses and immune cell differentiation, but its involvement in shaping the tumor immune microenvironment of colorectal cancer remains unclear. This study demonstrated that USP15 is overexpressed in colorectal cancer and correlated with a poor prognosis. Employing colon orthotopic and metastatic tumor models, we performed loss- and gain-of-function assays for USP15 and revealed that overexpression of USP15 promotes tumor progression by increasing the abundance of myeloid-derived suppressor cells (MDSC) and decreasing the presence of CD8+ T cells in the tumor microenvironment. Through in vitro co-culture models and rescue experiments, we observed that tumoral USP15 decreased T-cell abundance by promoting MDSC recruitment rather than directly affecting T cells. Mechanistically, we found that USP15 deubiquitinated SMYD3, thereby activating H3K4me3-mediated transcription and the release of CCL2, which subsequently recruited MDSCs. Treatment with a USP15 inhibitor improved the efficacy of PD-1 blockade in colorectal cancer models. In a cohort of patients with colorectal cancer undergoing immunotherapy, we observed that those with high USP15 expression had a poor response to anti-PD-1 therapy. In summary, this research explored how USP15 facilitates the recruitment of MDSCs and identified it as a promising target for enhancing immunotherapy in colorectal cancer.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1226-1245"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-Cell Analysis of Posttranslational Modifications Identifies Immunosuppressive Macrophage Subtypes in the HBV-Positive Hepatocellular Carcinoma Microenvironment. 翻译后修饰的单细胞分析鉴定了hbv阳性肝细胞癌微环境中的免疫抑制巨噬细胞亚型。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-01 DOI: 10.1158/2326-6066.CIR-24-1298

Huakan Zhao, Ran Ren, Xi Zhang, Mengtao Zhan, Jinwei Cui, Jun Zhang, Xi Liu, Lei Wu, Yu Chen, Yu Zhou, Yang Xiao, Jiangang Zhang, Yang Chen, Lu Zheng, Bing Sun, Yongsheng Li

{"title":"Single-Cell Analysis of Posttranslational Modifications Identifies Immunosuppressive Macrophage Subtypes in the HBV-Positive Hepatocellular Carcinoma Microenvironment.","authors":"Huakan Zhao, Ran Ren, Xi Zhang, Mengtao Zhan, Jinwei Cui, Jun Zhang, Xi Liu, Lei Wu, Yu Chen, Yu Zhou, Yang Xiao, Jiangang Zhang, Yang Chen, Lu Zheng, Bing Sun, Yongsheng Li","doi":"10.1158/2326-6066.CIR-24-1298","DOIUrl":"10.1158/2326-6066.CIR-24-1298","url":null,"abstract":"Analysis of posttranslational modifications (PTM) of proteins can provide new insights, beyond those obtained from analysis of protein levels, for understanding the tumor microenvironment (TME). The characteristics of PTMs in immune cells, along with their spatial distribution, have not been comprehensively integrated, which impedes our understanding of the complexity and heterogeneity of the TME in hepatocellular carcinoma (HCC). In this study, we used a strategy that combines antibodies for specific PTMs with mass cytometry and mass spectrometry technologies to identify PTMs at single-cell resolution. We found that the phosphorylation status of M2 macrophages was substantially altered in tumor tissues from patients with hepatitis B virus (HBV)-positive HCC. Utilizing the expression profiles of site-specific phospho-heat shock protein 27, signal transducer and activator of transcription 1, and tripartite motif-containing protein 28, we classified M2 macrophages into four distinct subtypes: M2-P0 (absence of any of the three phospho-proteins), M2-P1 (presence of one of the three phospho-proteins), M2-P2 (presence of two of the three phospho-proteins), and M2-P3 (presence of all three phospho-proteins). The spatial relationships and functional characteristics of these M2 macrophage subpopulations were assessed using single-cell PTM omics. The abundance of the M2-P2 and M2-P3 subtypes was closely associated with an immunosuppressive TME and responsiveness to immunotherapy in HBV+ HCC. Overall, this study introduces a single-cell PTM-omics approach that uncovers subtypes of macrophages associated with immunotherapeutic responses in HBV+ HCC and provides valuable insights into the immunosuppressive TME of HCC.","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1303-1317"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors. 从文献的亮点抽样：文章推荐从我们的副和高级编辑。

IF 8.2 1区医学

Cancer immunology research Pub Date : 2025-08-01 DOI: 10.1158/2326-6066.CIR-13-8-WWR

引用次数: 0