Experimental Hematology & Oncology最新文献

{"title":"Structural basis of FpGalNase and its combination with FpGalNAcDeAc for efficient A-to-O blood group conversion.","authors":"Meiling Zhou, Kaishan Luo, Chao Su, Yan Sun, Zuyan Huang, Shuo Ma, Xun Gao, Jiwei Wang, Chen Zhang, Pengcheng Han, Guoqiu Wu","doi":"10.1186/s40164-025-00599-7","DOIUrl":"https://doi.org/10.1186/s40164-025-00599-7","url":null,"abstract":"<p><p>Transfusion safety and blood typing continue to present significant challenges in clinical practice, including risks of incorrect blood transfusions and blood shortages. One promising solution is the enzymatic conversion of all red blood cell (RBC) types into universal O-type RBCs. However, the major obstacle to this strategy is the relatively low catalytic efficiency of the enzymes involved. In this study, we investigated two enzymes from Flavonifractor plautii, N-acetylgalactosamine deacetylase (FpGalNAcDeAc) and galactosaminidase (FpGalNase), which demonstrate synergistic activity in efficiently converting A-type RBCs to O-type. We optimized treatment conditions, achieving over 99% conversion in just five minutes using phosphate buffer saline and a 16 nM enzyme concentration. Additionally, we engineered two fusion proteins, FpGalNAcDeAc-FpGalNase and FpGalNase-FpGalNAcDeAc, which showed a 28-fold increase in catalytic efficiency compared to the enzyme mixture. Using cryo-electron microscopy, we resolved the full-length structure of FpGalNase, identifying critical active site residues involved in its catalytic mechanism. This study provides essential structural and biochemical insights for clinical applications in blood group conversion, offering a promising approach for producing universal O-type RBCs.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"7"},"PeriodicalIF":9.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037732","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}

{"title":"Construction and characterization of chimeric FcγR T cells for universal T cell therapy.","authors":"Juanjuan Zhao, Manling Chen, Xudong Li, Zhaoqi Chen, Wei Li, Rongqun Guo, Min Wang, Zhongxing Jiang, Yongping Song, Jianxiang Wang, Delong Liu","doi":"10.1186/s40164-025-00595-x","DOIUrl":"10.1186/s40164-025-00595-x","url":null,"abstract":"<p><strong>Background: </strong>Several approaches are being explored for engineering off-the-shelf chimeric antigen receptor (CAR) T cells. In this study, we engineered chimeric Fcγ receptor (FcγR) T cells and tested their potential as a versatile platform for universal T cell therapy.</p><p><strong>Methods: </strong>Chimeric FcγR (CFR) constructs were generated using three distinct forms of FcγR, namely CD16A, CD32A, and CD64. The functionality of CFR T cells was evaluated through degranulation assays, specific target lysis experiments, in vitro cytokine production analysis, and assessment of tumor xenograft destruction specificity in mouse models using different monoclonal antibodies (MoAbs).</p><p><strong>Results: </strong>Three types of CFR T cells were engineered, 16s3, 32-8a, 64-8a CFR T cells. In the presence of rituximab (RTX), cytotoxicity of all three types of CFR T cells against CD20⁺ Raji-wt, K562-CD20⁺, and primary tumor cells was significantly higher than that of the mock T cells (P < 0.001). When herceptin was used, all three types of CFR T cells exhibited significant cytotoxicity against HER2⁺ cell lines of SK-BR-3, SK-OV-3, and HCC1954 (P < 0.001). The cytotoxicity of 64-8a CFR T cells was significantly inhibited by free human IgG at a physiological dose (P < 0.001), which was not observed in 16s3, 32-8a CFR T cells. Compared to 32-8a CFR T cells, 16s3 CFR T cells exhibited more prolonged cytotoxicity than 32-8a CFR T cells (P < 0.01). In in vivo assays using xenograft models, 16s3 CFR T cells significantly prolonged the survival of mice xenografted with Raji-wt cells in the presence of RTX (P < 0.001), and effectively reduced tumor burden in mice xenografted with SK-OV-3 cells in the presence of herceptin (P < 0.05). No significant non-specific cytotoxicity of CFR T cells was found in vivo.</p><p><strong>Conclusion: </strong>The anti-tumor effects of the CFR T cells in vitro and in xenograft mouse models are mediated by specific MoAbs such as RTX and herceptin. The CFR T cells therefore have the features of universal T cells with specificity directed by MoAbs. 16s3 CFR T cells are chosen for clinical trials.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"6"},"PeriodicalIF":9.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983248","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}

{"title":"Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer.","authors":"Sharon Pei Yi Chan, Celestia Pei Xuan Yeo, Boon Hao Hong, Evelyn Mui Cheng Tan, Chaw Yee Beh, Eugenia Li Ling Yeo, Dennis Jun Jie Poon, Pek Lim Chu, Khee Chee Soo, Melvin Lee Kiang Chua, Edward Kai-Hua Chow","doi":"10.1186/s40164-024-00590-8","DOIUrl":"10.1186/s40164-024-00590-8","url":null,"abstract":"<p><strong>Background: </strong>Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite the addition of chemotherapy to radiotherapy to enhance its tumoricidal effects, almost a third of HNC patients suffer from locoregional relapses. Salvage therapy options for such recurrences are limited and often suboptimal, partly owing to divergent tumor and microenvironmental factors underpinning radioresistance. In this study, we utilized a combinatorial functionomics approach, the Quadratic Phenotypic Optimization Platform (QPOP), to rationally design drug pairings that exploit the molecular fingerprint and vulnerability of established in vitro isogenic radioresistant (RR)-HNC models.</p><p><strong>Methods: </strong>A QPOP-specific protocol was applied to RR-HNC models to rank and compare all possible drug combinations from a 12-drug set comprising standard chemotherapy, small molecule inhibitors and targeted therapies specific to HNC. Drug combination efficacy was evaluated by computing combination index scores, and by measuring apoptotic response. Drug targeting was validated by western blot analyses, and the Comet assay was used to quantify DNA damage. Enhanced histone deacetylase inhibitor (HDACi) efficacy in RR models was further examined by in vivo studies, and genetic and chemical inhibition of major Class I/II HDACs. Regulatory roles of HDAC6/SP1 axis were investigated using immunoprecipitation, gel shift and ChIP-qPCR assays. Comparative transcriptomic analyses were employed to determine the prognostic significance of targeting HDAC6.</p><p><strong>Results: </strong>We report the therapeutic potential of combining panobinostat (pan-HDAC inhibitor) with AZD7762 (CHK1/2 inhibitor; AstraZeneca) or ionizing radiation (IR) to re-sensitize RR-HNC cells and showed increased DNA damage underlying enhanced synergy. We further refined this RR-specific drug combination and prioritized HDAC6 as a targetable dependency in reversing radioresistance. We provide mechanistic insights into HDAC6-mediated regulation via a crosstalk involving SP1 and oncogenic and repair genes. From two independent patient cohorts, we identified a four-gene signature that may have discriminative ability to predict for radioresistance and amenable to HDAC6 inhibition.</p><p><strong>Conclusion: </strong>We have uncovered HDAC6 as a promising molecular vulnerability that should be explored to treat RR-HNC.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"5"},"PeriodicalIF":9.4,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970317","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}

{"title":"Biomechanics in the tumor microenvironment: from biological functions to potential clinical applications.","authors":"Hao Peng, Zheng Chao, Zefeng Wang, Xiaodong Hao, Zirui Xi, Sheng Ma, Xiangdong Guo, Junbiao Zhang, Qiang Zhou, Guanyu Qu, Yuan Gao, Jing Luo, Zhihua Wang, Jing Wang, Le Li","doi":"10.1186/s40164-024-00591-7","DOIUrl":"10.1186/s40164-024-00591-7","url":null,"abstract":"<p><p>Immune checkpoint therapies have spearheaded drug innovation over the last decade, propelling cancer treatments toward a new era of precision therapies. Nonetheless, the challenges of low response rates and prevalent drug resistance underscore the imperative for a deeper understanding of the tumor microenvironment (TME) and the pursuit of novel targets. Recent findings have revealed the profound impacts of biomechanical forces within the tumor microenvironment on immune surveillance and tumor progression in both murine models and clinical settings. Furthermore, the pharmacological or genetic manipulation of mechanical checkpoints, such as PIEZO1, DDR1, YAP/TAZ, and TRPV4, has shown remarkable potential in immune activation and eradication of tumors. In this review, we delved into the underlying biomechanical mechanisms and the resulting intricate biological meaning in the TME, focusing mainly on the extracellular matrix, the stiffness of cancer cells, and immune synapses. We also summarized the methodologies employed for biomechanical research and the potential clinical translation derived from current evidence. This comprehensive review of biomechanics will enhance the understanding of the functional role of biomechanical forces and provide basic knowledge for the discovery of novel therapeutic targets.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"4"},"PeriodicalIF":9.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970316","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}

{"title":"A cohort-based multi-omics identifies nuclear translocation of eIF5B /PD-L1/CD44 complex as the target to overcome Osimertinib resistance of ARID1A-deficient lung adenocarcinoma.","authors":"Dantong Sun, Helei Hou, Feiyue Feng, Weizheng Wu, Jingyu Tan, Tongji Xie, Jiayu Liu, Jinsong Wang, Haili Qian, Junling Li, Puyuan Xing","doi":"10.1186/s40164-024-00594-4","DOIUrl":"https://doi.org/10.1186/s40164-024-00594-4","url":null,"abstract":"<p><strong>Background: </strong>Osimertinib has emerged as a critical element in the treatment landscape following recent clinical trials. Further investigation into the mechanisms driving resistance to Osimertinib is necessary to address the restricted treatment options and survival advantages that are compromised by resistance in patients with EGFR-mutated lung adenocarcinoma (LUAD).</p><p><strong>Methods: </strong>Spatial transcriptomic and proteomic analyses were utilized to investigate the mechanisms of Osimertinib resistance. Co-IP, MS, RNA-seq, ChIP-seq, RIP-seq, and ATAC-seq were performed in cell lines to further explore the mechanism. To validate the findings, in vitro and in vivo molecular experiments were conducted.</p><p><strong>Results: </strong>We found that the ARID1A deficiency results in resistance to Osimertinib by hindering programmed cell death through the EZH2/PTEN/E2F1 axis. This altered axis influences PD-L1 transcription through E2F1-mediated promoter activation and PD-L1 translation via the MDM2/eIF5B/PD-L1 axis. Subsequently, ARID1A deficiency results in increased expression of eIF5B and Importin-β1, promoting PD-L1 nuclear-translocation. The nuclear PD-L1 (nPD-L1) interacts with CD44, leading to nPD-L1 complex formation, activation of the RASGEF1A promoter, initiation of the Ras pathway, and contributing to Osimertinib resistance. Targeting the transcription, translation and nuclear-translocation of PD-L1 using lipid nanoparticles (LNPs) overcomes ARID1A deficiency-induced resistance.</p><p><strong>Conclusion: </strong>ARID1A deficiency promotes PD-L1 nuclear translocation and induces Osimertinib resistance.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"3"},"PeriodicalIF":9.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947144","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}

{"title":"Prominent efficacy and good safety of sequential CD19 and CD22 CAR-T therapy in relapsed/refractory adult B-cell acute lymphoblastic leukemia.","authors":"Tingting Yang, Yetian Dong, Mingming Zhang, Jingjing Feng, Shan Fu, Pingnan Xiao, Ruimin Hong, Huijun Xu, Jiazhen Cui, Simao Huang, Guoqing Wei, Delin Kong, Jia Geng, Alex H Chang, He Huang, Yongxian Hu","doi":"10.1186/s40164-024-00593-5","DOIUrl":"https://doi.org/10.1186/s40164-024-00593-5","url":null,"abstract":"<p><strong>Background: </strong>Sequential CD19 and CD22 chimeric antigen receptor (CAR)-T cell therapy offers a promising approach to antigen-loss relapse in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL); however, research in adults remains limited.</p><p><strong>Methods: </strong>This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between November 2020 and November 2023 (ChiCTR2100053871). Key endpoints included the adverse event incidence, overall survival (OS), and leukemia-free survival (LFS).</p><p><strong>Results: </strong>Twenty-three patients with a median age of 58.1 years (range 25.9-75.0) were enrolled. High-risk cytogenetic and genomic aberrations were identified in 43.5% of patients, and five patients had baseline extramedullary disease (EMD). The median interval between the two infusions was 3.8 months. Grade ≥ 3 hematological adverse events occurred at comparable rates after both infusions. Cytokine release syndrome was observed in 78.3% and 39.1% of patients after CD19 and CD22 CAR-T therapy, respectively. Two patients experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T, and no ICANS was reported during CD22 CAR-T. The median OS was not reached with a median follow-up of 19.4 months (range 8.7-45.6), while the median LFS was 20.8 months. OS and LFS rates were 91.3% and 67.1% at 1 year and 58.6% and 47.0% at 2 years, respectively. Eight patients experienced relapse, with the cumulative incidence of relapse being 28.6% at 1 year and 42.5% at 2 years. Higher baseline leukemia burden (≥ 64% bone marrow blasts) and the presence of EMD were significant risk factors for inferior OS and LFS, respectively.</p><p><strong>Conclusions: </strong>Sequential CAR-T cell therapy demonstrated durable efficacy and a manageable safety profile in R/R B-ALL, providing a viable option to address antigen-loss relapse and improve long-term outcomes in high-risk adult patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"2"},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926950","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}

{"title":"Safety and efficacy of CD33-targeted CAR-NK cell therapy for relapsed/refractory AML: preclinical evaluation and phase I trial.","authors":"Ruihao Huang, Xiaoqi Wang, Hongju Yan, Xu Tan, Yingying Ma, Maihong Wang, Xiao Han, Jia Liu, Li Gao, Lei Gao, Guangjun Jing, Cheng Zhang, Qin Wen, Xi Zhang","doi":"10.1186/s40164-024-00592-6","DOIUrl":"10.1186/s40164-024-00592-6","url":null,"abstract":"<p><strong>Background: </strong>Due to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by \"off-target\" effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells.</p><p><strong>Methods: </strong>The CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18-65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy.</p><p><strong>Results: </strong>The CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable to that of CD33 CAR-T cells but showed limited toxicity to hematopoietic stem cells (HSCs). Ten patients, with a median of five prior lines of treatment, completed the efficacy evaluation (range, 3-8). No grade 3-4 adverse events were observed, except bone marrow suppression, which was relieved within one month. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) were reported following CAR-NK cell infusion. Only one patient experienced grade 2 cytokine release syndrome (CRS) and presented with persistent fever. By day 28, six of ten patients had achieved minimal residual disease (MRD)-negative complete remission.</p><p><strong>Conclusions: </strong>Our preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML. Expanded samples and longer follow-up periods are needed to provide further efficacy data.</p><p><strong>Trial registration: </strong>NCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"1"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921267","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}

{"title":"AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.","authors":"HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen","doi":"10.1186/s40164-024-00586-4","DOIUrl":"10.1186/s40164-024-00586-4","url":null,"abstract":"<p><p>Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. We report on AOH1996 (AOH), an oral compound targeting cancer-associated PCNA, which shows significant antileukemic activity. AOH inhibited growth in AML cell lines and primary CD34 + CD38 - blasts (LSC-enriched) in vitro while sparing normal hematopoietic stem cells (HSCs). In vivo, AOH-treated mice demonstrated prolonged survival compared to controls (50 vs. 35 days; p < 0.0001) with reduced LSC burden, as shown in secondary transplants (42 vs. 30 days, p < 0.0001). Mechanistically, AOH disrupted mitochondrial PCNA's binding to the OPA1 protein, enhancing OPA1's interaction with its E3 ligase, MARCH5, which led to OPA1 degradation. This process reduced mitochondrial length, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby inhibiting LSC expansion. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"123"},"PeriodicalIF":9.4,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893288","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}

{"title":"Disrupting Notch signaling related HES1 in myeloid cells reinvigorates antitumor T cell responses.","authors":"Myung Sup Kim, Hyeokgu Kang, Jung-Hwan Baek, Moon-Gyu Cho, Eun Joo Chung, Seok-Jun Kim, Joon-Yong Chung, Kyung-Hee Chun","doi":"10.1186/s40164-024-00588-2","DOIUrl":"10.1186/s40164-024-00588-2","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages (TAMs) are immunosuppressive cells within the tumor microenvironment (TME) that hinder anti-tumor immunity. Notch signaling is a pathway crucial for TAM differentiation and function. Here, we investigate the role of HES1, a downstream target of Notch signaling, in TAM-mediated immunosuppression and explore its potential as a target for cancer immunotherapy.</p><p><strong>Methods: </strong>In this work, we constructed conditional Hes1 knockout mice to selectively delete Hes1 in TAMs. We further analyzed the TME composition, T cell infiltration and activation, and anti-tumor effects in these mice, both alone and in combination with PD-1 checkpoint blockade.</p><p><strong>Results: </strong>Our study showed that expression levels of Notch target Hes1 were increase in TAMs and mice with conditional knockout of Hes1 gene in TAMs exhibited decreased tumor growth, with increased infiltration and activation of cytotoxic T cells in tumors. Expression of tumor promoting factors was critically altered in Hes1-conditional KO TAMs, leading to the improved tumor microenvironment. Notably, arginase-1 expression was decreased in Hes1-conditional KO mice. Arg1 is known to deplete arginine and deactivate T cells in the TME. Administration of anti-PD-1 monoclonal antibody inhibited tumor growth to a greater extent in Hes1-conditional KO mice than in WT mice.</p><p><strong>Conclusions: </strong>We identified a pivotal role for the Notch signaling pathway in shaping TAM function, suggesting that T-cell dysfunction in the TME is caused when the Notch target, HES1, in TAMs is upregulated by tumor-associated factors (TAFs), which, in turn, increases the expression of arginase-1. Targeting HES1 in TAMs appears to be a promising strategy for cancer immunotherapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"122"},"PeriodicalIF":9.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863890","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}

{"title":"Identification of a novel subtype of SPP1 + macrophages expressing SIRPα: implications for tumor immune evasion and treatment response prediction.","authors":"Kun Chen, Yida Li, Jianjiao Ni, Xi Yang, Yue Zhou, Yechun Pang, Ruiting Ye, Hongru Chen, Silai Yu, Peng Wang, Zhengfei Zhu","doi":"10.1186/s40164-024-00587-3","DOIUrl":"10.1186/s40164-024-00587-3","url":null,"abstract":"<p><strong>Background: </strong>SPP1 + macrophages are among the major phagocytic cells, yet promoting tumor immune evasion and predicting unfavorable prognosis, in various cancer types. Meanwhile, the predictive value of the abundance of SPP1 + macrophages in patients receiving immunotherapy remains debatable, indicating the potential existence of subtypes of SPP1 + macrophages with diverse biological functions.</p><p><strong>Methods: </strong>The single cell RNA sequencing data of myeloid cells integrated from several cancers including esophageal squamous cell carcinoma was analyzed for characterizing the function and cellular interactions of SPP1 + macrophages expressing SIRPα. Multiplexed immunohistochemistry was used to quantify the quantity and spatial distribution of SPP1 + macrophages expressing SIRPα. Kaplan-Meier method was used for survival analysis. In vitro and in vivo studies investigating the function of SPP1 + macrophages were performed.</p><p><strong>Results: </strong>SPP1 + macrophages possessed a high phagocytic signature and could engulf more tumor cells in vitro and in vivo. SIRPα expression could represent the phagocytic activity of SPP1 + macrophages and delineated subsets of SPP1 + macrophages with different functions. SPP1 + SIRPα + macrophages showed close spatial distance to tumor cells and positively correlated with PD1 + CD8 + T cells. A high abundance of SPP1 + SIRPα + macrophages at baseline corresponded to patients' response to PD-1/PD-L1 inhibitors.</p><p><strong>Conclusion: </strong>A novel subtype of SPP1 + macrophages expressing SIRPα was identified and their abundance predicted patients' response to PD-1/PD-L1 inhibitors.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"119"},"PeriodicalIF":9.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853532","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}