Experimental Hematology & Oncology最新文献

{"title":"A proinflammatory response and polarized differentiation of stromal elements characterizes the murine myeloma bone marrow niche.","authors":"Hussein Ghamlouch, Dylan C Gagler, Patrick Blaney, Eileen M Boyle, Yubao Wang, Jason Avigan, Jinyoung Choi, Ola Landgren, Aristotelis Tsirigos, Francesco Maura, Gareth J Morgan, Faith E Davies","doi":"10.1186/s40164-025-00606-x","DOIUrl":"10.1186/s40164-025-00606-x","url":null,"abstract":"<p><strong>Background: </strong>The bone marrow (BM) niche contains non-hematopoietic elements including mesenchymal stromal cells (MSC) and bone marrow endothelial cells (BMEC) which provide mechanical support, and control hematopoietic cell growth and differentiation. Although it is known that multiple myeloma (MM) cells interact closely with the BM microenvironment, little is known about the impact of MM on non-hematopoietic niche-forming cells.</p><p><strong>Methods: </strong>To address the role of the niche in MM pathogenesis, we utilized the 5TGM1 murine model. During the asymptomatic precursor stage of the model, we isolated the rare non-hematopoietic cells and performed single cell RNA sequencing. Using in-silico methods we characterized the individual cellular components of the niche, their relative abundance and differentiation state before and after exposure to MM cells as well as their intercellular interactions.</p><p><strong>Results: </strong>MM engraftment increased the abundance of MSC-lineage cells, BMECs and enhanced endothelial to mesenchymal transition. An inflammatory and oxidative stress signal was identified together with polarization of MSC differentiation away from osteocyte formation towards adipocytes which provide growth factors that are known to support MM expansion. BMEC differentiation was polarized towards sinusoidal endothelial cells with a pro-angiogenic/pro-inflammatory phenotype.</p><p><strong>Conclusions: </strong>MM cells impact the BM niche by generating a pro-inflammatory microenvironment with MSC differentiation being changed to generate cell subsets that favor MM growth and survival. In order to induce remission and improve long-term outcome for MM patients these inflammatory and oxidative stress signals need to be reduced and normal niche differentiation trajectories restored.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"22"},"PeriodicalIF":9.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515200","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":"Suppression of CYLD by HER3 confers ovarian cancer platinum resistance via inhibiting apoptosis and by inducing drug efflux.","authors":"Ye Zhang, Jian-Ge Qiu, Wei Wang, Fan-Li Sun, Xue Wang, Wen-Jing Liu, Xiao-Yu Jia, Hongbin Ji, Lin Wang, Bing-Hua Jiang","doi":"10.1186/s40164-025-00620-z","DOIUrl":"10.1186/s40164-025-00620-z","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) is the most pathogenic gynecological malignant tumor in the world. Due to the difficulty of early diagnosis, most of patients developed chemo-resistance and recurrence during/after chemotherapy.</p><p><strong>Methods: </strong>CCK8 and flow cytometry were utilized to assess drug sensitivity and apoptosis in parental and drug resistant cell lines. CYLD knockdown or overexpressed cells were employed to investigate its regulatory involvement in DDP resistance. Clinical tumor samples have been utilized to investigate the clinical relevance of CYLD. The drug synergistic effects were investigated through drug combination methods and a nude mice model with ABCB1 inhibitor or HER3 inhibitor.</p><p><strong>Results: </strong>In this study, we found that CYLD levels were significantly reduced in DDP-resistant cancer tissues and cells compared to the normal tissues and cells. CYLD knockdown in DDP-sensitive cells was sufficient to converse the cells to become DDP resistant by reducing cell apoptosis through increasing Bcl-XL and inhibiting Bax, and by increasing drug efflux via upregulating ABCB1 expression. HER3 expression levels were substantially higher in resistant cancer tissues and cells, and HER3 was the upstream facilitator of suppressing CYLD expression via STAT3 signaling. Furthermore, overexpression of CYLD in resistant cells increased sensitivity to platinum-based chemotherapy both in vitro and in vivo. ABCB1 was a key downstream target of CYLD for regulating tumor growth and therapeutic resistance both in vitro and in vivo, CYLD knockdown promoted the translocation of p65 to nucleus which increased ABCB1 expression through transcriptional activation. High expression levels of HER3 rendered CYLD suppression, consequently, mediated DDP resistance by blocking cell apoptosis pathways and promoting the drug efflux in ovarian cancer.</p><p><strong>Conclusions: </strong>Our findings identify novel HER3/CYLD/ABCB1 axis that regulate tumor growth and DDP resistance, which may be used as potential novel therapeutic target(s) to overcome ovarian cancer DDP resistance.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"21"},"PeriodicalIF":9.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515201","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":"Bridging therapy with histotripsy prior to liver transplantation for hepatocellular carcinoma: a first case report.","authors":"Melis Uysal, Chase J Wehrle, Christopher Coppa, Suneel Kamath, Smitha Krishnamurthi, Charles Martin, Mohamed El Hag, Mazhar Khalil, Masato Fujiki, Andrea Schlegel, Charles Miller, Koji Hashimoto, Federico Aucejo, David Ch Kwon, Jaekeun Kim","doi":"10.1186/s40164-025-00604-z","DOIUrl":"10.1186/s40164-025-00604-z","url":null,"abstract":"<p><strong>Background: </strong>Histotripsy is a novel, non-invasive, non-ionizing, and non-thermal ablation technique that disrupts tumors using acoustic cavitation. We report the first use of Histotripsy as bridging therapy prior to liver transplant for hepatocellular carcinoma (HCC) treated with histotripsy.</p><p><strong>Case presentation: </strong>A 59-year-old woman presented with Metabolic-Associated Steatotic Liver Disease (MASLD) cirrhosis (labMELD = 14), hepatic encephalopathy, and a single 2 cm OPTN V lesion in the left lateral segment consistent with HCC. The patient underwent histotripsy treatment of the lesion as bridging therapy before receiving liver transplantation. Histopathology analysis of the explanted liver showed total necrosis of the treated area, with no residual viable tissue tumor.</p><p><strong>Conclusion: </strong>This case demonstrates the potential utility of histotripsy as an effective bridging therapy for patients with combined cirrhosis and hepatocellular carcinoma (HCC) awaiting liver transplantation, with complete tumor necrosis on explant pathology demonstrating its therapeutic efficacy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"20"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500096","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":"Alcohol accelerates the development of esophageal squamous cell carcinoma through elevated Gram-negative bacteria in peripheral circulation.","authors":"Zehua Zhang, Le Kang, Yanfen Gu, Zhuyun Leng, Tao Chen, Meidong Xu","doi":"10.1186/s40164-025-00617-8","DOIUrl":"10.1186/s40164-025-00617-8","url":null,"abstract":"<p><p>Alcohol consumption is intricately linked to the incidence of esophageal squamous cell carcinoma (ESCC). This study comprehensively investigates the role of alcohol-induced microbial alterations in ESCC progression. A retrospective analysis of 328 patients demonstrated that alcohol consumption markedly increases the risk of ESCC and boosts the expression of the proliferation marker Ki67. Patients with alcohol-related ESCC exhibited substantially higher blood microbiome diversity, characterized by the dominance of Gram-negative bacteria, and elevated serum lipopolysaccharides (LPS) levels. In a mouse model, alcohol consumption not only augmented tumor burden but also compromised gut barrier integrity, facilitating bacterial translocation. Significant elevations in Gram-negative bacteria, such as Bacteroidales in the blood and Escherichia coli in esophageal tissues, were observed. Mechanistically, alcohol and LPS synergistically activated pro-inflammatory pathways, including TNF, TLR, NF-κB, and MAPK, which fueled ESCC cell proliferation. Meanwhile, LPS triggered necroptosis in normal esophageal epithelial cells. These findings reveal that alcohol-induced microbial dysbiosis in peripheral circulation and LPS-mediated inflammatory responses form a novel pathogenic mechanism in ESCC. Targeting Gram-negative bacteria and LPS could provide a promising therapeutic strategy for managing alcohol-related ESCC. Further research is urgently warranted to explore the interaction between microbial changes and the tumor microenvironment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"19"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500095","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":"Molecular profiling of skin cells identifies distinct cellular signatures in radiation-induced skin injury across various stages in the murine dataset.","authors":"Hongxuan Yu, Tao Zhong, Ying Xu, Zengfu Zhang, Jiachun Ma, Jupeng Yuan, Minglei Wang, Meng Wu, Jinming Yu, Yuequn Ma, Dawei Chen","doi":"10.1186/s40164-025-00596-w","DOIUrl":"10.1186/s40164-025-00596-w","url":null,"abstract":"<p><strong>Background: </strong>Radiation-induced skin injury (RISI) commonly manifests in cancer patients undergoing radiotherapy (RT). However, a universally accepted standard for treating radiation injury has not yet been established. Our objective was to provide a detailed molecular overview of skin pre- and post-radiation therapy, aiming to enhance our understanding of the subclusters and molecular mechanisms contributing to radiodermatitis.</p><p><strong>Methods: </strong>C57BL/6 mice were subjected to a single fraction (20 Gy) of RT targeting the right dorsal skin. We then employed integrated single-cell RNA sequencing (scRNA-seq) to analyze skin samples from mice at 7 and 30 days after radiation exposure, as well as from non-irradiated mice. The Seurat analysis pipeline, Cellchat, SCP, and ssGSEA were used to define the cell types and mechanisms involved in radiation-induced skin injury. Reverse transcription polymerase chain reaction (RT-PCR), multiplex immunofluorescent staining, and other datasets (GSE130183, GSE193564, and GSE193807) were used to validate our findings.</p><p><strong>Results: </strong>Thirty-two distinct cell clusters encompassing 71,412 cells were identified. We discovered that cycling keratinocytes (KCs), with the BMP signaling pathway enriched, could activate the Wnt pathway, as well as the SMAD pathways, driving the wound healing and fibrosis processes in RISI. Terminally differentiated secretory-papillary fibroblasts (Fibs) are capable of attracting immune cells, which contributes to the pathogenesis of RISI. Lymphatic endothelial cells (ECs) with pro-inflammatory properties play a critical role in the pathogenesis of RISI by facilitating leukocyte migration. Our analysis also highlighted enhanced ligand-receptor interactions, notably the interactions between chemokines like CXCL10, CCL2, and ACKR1, across subclusters of inflammatory KCs, Fibs, ECs, and immune cells, underscoring their pivotal role in leukocyte recruitment in RISI.</p><p><strong>Conclusions: </strong>Cycling KCs, secretory-papillary Fibs, and lymphatic ECs play critical roles in RISI progression. Targeting the interactions of these subclusters with immune cells might help improve the severity of RISI. Furthermore, our study provides a valuable resource for understanding the interactions among immune cells in the context of RISI.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"18"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500097","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":"The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody-dependent cytotoxicity.","authors":"Sara Caratelli, Francesca De Paolis, Domenico Alessandro Silvestris, Silvia Baldari, Illari Salvatori, Apollonia Tullo, Giulia Lanzilli, Aymone Gurtner, Alberto Ferri, Cristiana Valle, Simona Padovani, Valeriana Cesarini, Tommaso Sconocchia, Loredana Cifaldi, Roberto Arriga, Giulio Cesare Spagnoli, Soldano Ferrone, Adriano Venditti, Piero Rossi, Graziano Pesole, Gabriele Toietta, Giuseppe Sconocchia","doi":"10.1186/s40164-025-00601-2","DOIUrl":"10.1186/s40164-025-00601-2","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck.</p><p><strong>Methods: </strong>The CD64/CD28/CD3ζ -SFG retroviral vector was used to produce viruses for T-cell transduction. T-cell expansion and differentiation were monitored via flow cytometry. Gene expression was assessed by RNA-seq. Bioenergetics were documented on a Seahorse extracellular flux analyzer. CD64/CD28/CD3ζ polarization was identified via confocal microscopy. Cytotoxicity was determined by MTT assay and bioluminescent imaging, and flow cytometry. Tridimensional antitumor activity of CD64/CD28/CD3ζ T cells was achieved by utilizing HCT116-GFP 3D spheroids via the IncuCyte S3 Live-Cell Analysis system. The intraperitoneal distribution and antitumor activity of NIR-CD64/CD28/CD3ζ and NIR-nontransduced T cells were investigated in CB17-SCID mice bearing subcutaneous FaDu Luc + cells by bioluminescent and fluorescent imaging. IFNγ was assessed by ELISA.</p><p><strong>Results: </strong>Compared to CD16/CD8a/CD28/CD3ζ T cells, CD32/CD8a/CD28/CD3ζ T cells, and non-transduced T cells, CD64/CD28/CD3ζ T cells exhibited the highest levels of cell expansion and persistence capacity. A total of 235 genes linked to cell division and 52 genes related to glycolysis were overexpressed. The glycolytic phenotype was confirmed by functional in vitro studies accompanied by preferential T-cell effector memory differentiation. Interestingly, oxamic acid was found to inhibit CD64-CR T cell proliferation, indicating the involvement of lactate. Upon CD64/CD28/CD3ζ T-cell conjugation with CRC cells, CD64/CD28/CD3ζ cells polarize at immunological synapses, leading to CRC cell death. CD64/CD28/CD3ζ T cells kill SCCHN cells, and in combination with the anti-B7-H3 mAb (376.96) or anti-EGFR mAb, these cells trigger antibody-dependent cellular cytotoxicity (ADCC) in vitro under 2D and 3D conditions. The 376.96 mAb combined with CD64/CD28/CD3ζ T cells had anti-SCCHN activity in vivo. In addition, they induce the upregulation of PD-L1 and HLA-DR expression in cancer cells via IFNγ. PD-L1 positive SCCHN cells in combination with anti-PD-L1 mAb and CD64-CR T cells were killed by ADCC, which enhanced direct cytotoxicity. These findings indicate that the glycolytic phenotype is involved in CD64-CR T cell proliferation/expansion. These cells mediate long-lasting HLA-independent cytotoxicity and ADCC in CRC and SCCHN cells.</p><p><strong>Conclusions: </strong>CD64/CD28/CD3ζ T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel FcγR ALs in cancer and healthy cells.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"17"},"PeriodicalIF":9.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439485","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":"IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response.","authors":"Mingyue Yao, Wenzhong Yan, Yafang Wang, Yu Zhao, Xiaowei Xu, Yujun Chen, Chengcheng Yu, Yingnian Li, Hualiang Jiang, Jie Shen, Jianjun Cheng, Chengying Xie","doi":"10.1186/s40164-025-00605-y","DOIUrl":"10.1186/s40164-025-00605-y","url":null,"abstract":"<p><strong>Background: </strong>Despite initial success with FLT3 inhibitors (FLT3is), outcomes for FLT3-ITD acute myeloid leukemia (AML) patients remain unsatisfactory, underscoring the need for more effective treatment options. Epigenetic modifications, such as histone acetylation, contribute to AML's onset and persistence, advocating the potential for epigenetic therapies. However, the poor specificity of pan-histone deacetylase inhibitors (HDACis) leads to undesirable adverse effects, prompting the need for isoform-specific HDACis. This study aims to explore the antileukemic activities and mechanisms of IHCH9033, a novel class I HDACi, alone or combined with FLT3i in FLT3-ITD AML.</p><p><strong>Methods: </strong>The viability of AML cell lines and primary AML cells treated with HDACis alone or in combination with FLT3i was detected by MTT or CCK8 assay. Flow cytometry was utilized to examine cell apoptosis, cell cycle progression and ROS production. RNA sequencing analysis, RT-qPCR, western blotting, and co-immunoprecipitation assays were employed to elucidate the molecule mechanisms. The in vivo anti-leukemia efficacy was tested in xenografted mice models derived from FLT3-ITD cell lines and primary AML patients.</p><p><strong>Results: </strong>Here, we identified IHCH9033, a novel selective class I HDACi, which exhibited an increased antitumor effect in FLT3-ITD AML through effectively eliminating leukemia burden and overcoming resistance to FLT3i. Mechanically, IHCH9033 selectively inhibited DNA repair in FLT3-ITD AML cells, leading to the accumulation of DNA damage that eventually resulted in cell cycle arrest and apoptosis. Additionally, IHCH9033 induced HSP90 acetylation, FLT3 ubiquitination, and proteasomal degradation of FLT3, thereby inhibiting FLT3 downstream signaling. Notably, IHCH9033 maintained its potency in both FLT3i-resistant AML cell lines and primary-resistant patient samples, and exerted strong synergy with the FLT3i quizartinib, leading to tumor regression in FLT3-ITD/TKD AML xenografts. In patient-derived xenografts, the treatment with IHCH9033, both alone and in combination, led to nearly complete eradication of the AML burden, without significant adverse effects.</p><p><strong>Conclusions: </strong>Our study shows that IHCH9033, a novel class I HDACi with a desirable pharmacological profile, is a promising drug candidate for FLT3-ITD AML, and suggests a strategy of combining class I HDACis and FLT3is in AML clinical trials to increase efficacy and overcome resistance, thus potentially providing a curative treatment option.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"15"},"PeriodicalIF":9.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425385","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":"Engineered oncolytic virus coated with anti-PD-1 and alendronate for ameliorating intratumoral T cell hypofunction.","authors":"Yufu Zhu, Xuefeng Zhang, Jiaqi Jin, Xiaoqian Wang, Yang Liu, Jian Gao, Diancheng Hang, Lin Fang, Hengzhu Zhang, Hongmei Liu","doi":"10.1186/s40164-025-00611-0","DOIUrl":"10.1186/s40164-025-00611-0","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is a highly aggressive and devastating primary brain tumor that is resistant to conventional therapies. Oncolytic viruses represent a promising therapeutic approach for glioblastoma by selectively lysing tumor cells and eliciting an anti-tumor immune response. However, the clinical efficacy of oncolytic viruses is often hindered by challenges such as short persistence, host antiviral immune responses, and T cell dysfunction.</p><p><strong>Methods: </strong>We have developed a novel therapeutic strategy by \"dressing\" oncolytic viruses with anti-PD-1 antibodies and alendronate (PD-1/Al@OV) to prevent premature clearance of the oncolytic viruses and enhance T cell function, thereby improving immunotherapy outcomes against glioma.</p><p><strong>Results: </strong>We found that in the high reactive oxygen species environment of the tumor, PD-1/Al@OV disassembled to release oncolytic viruses, anti-PD-1, and alendronate. The released anti-PD-1 blocked the PD-1/PD-L1 pathway, activating T cells; the alendronate eliminated tumor-associated macrophages, increasing the concentration of oncolytic viruses; and the oncolytic viruses directly lysed cancer cells, enhancing intratumoral T cell infiltration.</p><p><strong>Conclusion: </strong>This approach effectively improved the immunosuppressive microenvironment of glioblastoma and achieved a robust anti-tumor effect. Consequently, this study presents a novel strategy for immune combination therapy and the improvement of the glioblastoma immune microenvironment, thereby offering new prospects for the clinical application of oncolytic viruses.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"16"},"PeriodicalIF":9.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425380","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":"Distinct response to IL-1β blockade in liver- and lung-specific metastasis mouse models of pancreatic cancer with heterogeneous tumor microenvironments.","authors":"Sophia Y Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Kaiyi Mu, Haley Zlomke, Michael Loycano, Rulin Wang, William R Burns, Juan Fu, Lei Zheng","doi":"10.1186/s40164-025-00607-w","DOIUrl":"10.1186/s40164-025-00607-w","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is characterized by a heterogeneous tumor microenvironment (TME). The mechanism by which this heterogeneity confers resistance against immunotherapy remains unclear. Interleukin- 1β (IL-1β) is a proinflammatory cytokine that regulates heterogeneous cancer associated fibroblast (CAF) phenotype and promotes an immunosuppressive TME. Anti-IL-1β monoclonal antibody significantly enhanced the anti-tumor activity of anti-PD-1 in a preclinical model of PDAC. However, clinical trials have shown limited activity of the anti-IL-1β and anti-PD-1 combination. Therefore, we hypothesize that anti-tumor immune response to the combination of anti-IL-1β and anti-PD-1 antibodies is context-dependent and would be affected by the TME heterogeneity in PDAC.</p><p><strong>Methods: </strong>Liver- and lung-specific metastasis mouse models of PDAC were used to investigate the antitumor activity of anti-IL-1β and anti-PD-1 antibodies alone or in combination by ultrasound examination and survival analysis. Their effects on the TME heterogeneity were assessed by flow cytometry and single nuclear RNA sequencing.</p><p><strong>Results: </strong>The combination of anti-IL-1β and anti-PD-1 antibodies does not slow primary tumor growth but prolongs overall survival and reduces lung metastasis rates in a PDAC orthotopic murine model with lung metastasis tropism. In contrast, combination therapy slows primary tumor growth and prolongs survival, but does not reduce liver metastasis rates in a PDAC murine orthotopic model with liver metastasis tropism. Flow cytometry analysis showed that the combination of anti-IL-1β and anti-PD-1 antibodies restores T cell activation negated by the monotherapies. Mechanistically, in the PDAC model with lung metastasis tropism, but not in the model with liver metastasis tropism, combination treatment reverses an increased trend of immunosuppressive myeloid cells as a result of monotherapy. Single-nuclear RNA sequencing analysis of both organ-specific tumor models demonstrated that anti-IL-1β treatment altered infiltration and function of CAF and immune cells differently. Furthermore, anti-IL-1β treatment modulated cytokine/chemokine ligand-receptor-receptor interactions in the models with different organ-specific metastasis distinctly.</p><p><strong>Conclusion: </strong>This study reveals the differential responses of organ-specific metastasis mouse models of PDAC with distinct TMEs to anti-IL-1β and anti-PD-1 treatments, suggesting that treatment response is context-dependent and affected by TME heterogeneity.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"13"},"PeriodicalIF":9.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413729","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":"CAR-macrophages targets CD26 to eliminate chronic myeloid leukemia stem cells.","authors":"Jiang Guoyun, Qin Yuefeng, Huang Zhenglan, Yuan Zuowei, Zhou Hongyan, Yuan Ying, Feng Wenli","doi":"10.1186/s40164-025-00608-9","DOIUrl":"10.1186/s40164-025-00608-9","url":null,"abstract":"<p><strong>Background: </strong>Chronic myeloid leukemia stem cells (CML-LSCs), which exhibit resistance to tyrosine kinase inhibitors (TKIs), are the leading cause of treatment failure and recurrence in chronic myeloid leukemia (CML). This highlights the urgent need for novel therapies aimed at eliminating these CML-LSCs. Chimeric antigen receptor macrophages (CAR-M) not only perform phagocytosis on target cells but also function as antigen-presenting cells, thereby activating the anti-tumor immune response.CD26 (dipeptidyl peptidase 4, DPP IV) is abundantly expressed in CML-LSCs and functions as a tumor-specific antigen (TSA) in CAR-M treatment. The purpose of this study is to evaluate CAR-M's efficacy in targeting CD26-positive CML cells and to develop a novel strategy for CML treatment.</p><p><strong>Methods: </strong>CD26 CAR-M was constructed using mouse-derived macrophage Raw264.7 cells. CD26 was overexpressed in CML cell lines BP210 and BP210-T315I. The targeting phagocytosis of CAR-M was verified using confocal microscopy and flow cytometry. X-ray was used to eliminate the tumorigenicity of CAR-M, and the safety of CAR-M was verified through CCK-8, clone formation assays, and animal experiments. To assess the anti-leukemia ability of CAR-M in the CML mouse model, the survival, peripheral blood white blood cell counts, and CML cell infiltration in the liver, spleen, and bone marrow (BM) were measured. Additionally, CD26 CAR-THP1 was constructed, and its phagocytic ability against CD26-positive cells NCI-H2452 was confirmed by confocal microscopy.</p><p><strong>Results: </strong>We successfully constructed CD26 CAR-M and validated its targeted phagocytosis of CD26-positive CML cells both in vitro and in vivo. The data indicate that CAR-M has higher phagocytic efficiency in CD26-positive CML cells than in CD26-negative cells. CAR-M-treated CML mice demonstrated extended survival and reduced CML invasion. In addition, CAR-THP1 demonstrated targeted phagocytosis of NCI-H2452 cells that normally express CD26.</p><p><strong>Conclusion: </strong>This study demonstrates that CD26 CAR-M effectively targets and phagocytizes CD26-positive CML cells, implying that targeting CD26 with CAR-M could be a viable method for eradicating CML-LSCs. Furthermore, our discoveries illuminate the potential application of CAR-M in treating hematological malignancies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"14"},"PeriodicalIF":9.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413535","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}