Molecular Therapy: Oncology最新文献_第4页

Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function 将 PD-1 排除在免疫突触之外：调节 T 细胞功能的新策略

Molecular Therapy: Oncology Pub Date : 2024-06-17 DOI: 10.1016/j.omton.2024.200839

Luke Yi Hao, Shalom Lerrer, Matthieu Paiola, Emily K. Moore, Yevgeniya Gartshteyn, Ruijiang Song, Michael Goeckeritz, Matilda J. Black, Shoiab Bukhari, Xizi Hu, Adam Mor

{"title":"Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function","authors":"Luke Yi Hao, Shalom Lerrer, Matthieu Paiola, Emily K. Moore, Yevgeniya Gartshteyn, Ruijiang Song, Michael Goeckeritz, Matilda J. Black, Shoiab Bukhari, Xizi Hu, Adam Mor","doi":"10.1016/j.omton.2024.200839","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200839","url":null,"abstract":"Targeting immune checkpoint receptors on T cells is a common cancer treatment strategy. Frequently, this is accomplished through antibodies targeting the ligand of inhibitory co-receptors. Blocking the immune checkpoint PD-1 binding to its ligands PD-L1 and PD-L2 prevents downstream signaling and enhances anti-tumor T cell responses. This approach improves cancer patients’ outcomes. However, only one-third of the patients respond to these treatments. To better understand the mechanism of anti-PD-1 antibodies, we explored the location of PD-1 within the immune synapse. Surprisingly, we discovered that anti-PD-1 antibodies, besides blocking the interaction between PD-1 and its ligands, also removed PD-1 from the synapse. We demonstrated a correlation between removing PD-1 from the synapse by anti-PD-1 antibodies and the extent of T cell activation. Interestingly, a short version of the anti-PD-1 antibody, F(ab′), failed to remove PD-1 from the synapse and activate T cells. Using the syngeneic tumor model, we showed a superior anti-tumor effect of the anti-PD-1 antibody over the shorter version of the same antibody. Our data indicate that anti-PD-1 antibodies activate T cells by removing PD-1 from the synapse, and changing the location of PD-1 or other immune receptors within the immune synapse could serve as an alternative, efficient approach to treat cancer.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141529194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comprehensive machine learning-based integration develops a novel prognostic model for glioblastoma 基于机器学习的综合集成开发出胶质母细胞瘤的新型预后模型

Molecular Therapy: Oncology Pub Date : 2024-06-17 DOI: 10.1016/j.omton.2024.200838

Qian Jiang, Xiawei Yang, Teng Deng, Jun Yan, Fangzhou Guo, Ligen Mo, Sanqi An, Qianrong Huang

{"title":"Comprehensive machine learning-based integration develops a novel prognostic model for glioblastoma","authors":"Qian Jiang, Xiawei Yang, Teng Deng, Jun Yan, Fangzhou Guo, Ligen Mo, Sanqi An, Qianrong Huang","doi":"10.1016/j.omton.2024.200838","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200838","url":null,"abstract":"In this study, we developed a new prognostic model for glioblastoma (GBM) based on an integrated machine learning algorithm. We used univariate Cox regression analysis to identify prognostic genes by combining six GBM cohorts. Based on the prognostic genes, 10 machine learning algorithms were integrated into 117 algorithm combinations, and the artificial intelligence prognostic signature (AIPS) with the greatest average C-index was chosen. The AIPS was compared with 10 previously published models by univariate Cox analysis and the C-index. We compared the differences in prognosis, tumor immune microenvironment (TIME), and immunotherapy sensitivity between the high and low AIPS score groups. The AIPS based on the random survival forest algorithm with the highest average C-index (0.868) was selected. Compared with the previous 10 prognostic models, our AIPS has the highest C-index. The AIPS was closely linked to the clinical features of GBM. We discovered that patients in the low score group had improved prognoses, a more active TIME, and were more sensitive to immunotherapy. Finally, we verified the expression of several key genes by western blotting and immunohistochemistry. We identified an ideal prognostic signature for GBM, which might provide new insights into stratified treatment approaches for GBM patients.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"144 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141505337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DARPin-fused T cell engager for adenovirus-mediated cancer therapy 用于腺病毒介导的癌症治疗的 DARPin 融合 T 细胞吸引器

Molecular Therapy: Oncology Pub Date : 2024-05-29 DOI: 10.1016/j.omton.2024.200821

Patrick C. Freitag, Jonas Kolibius, Ronja Wieboldt, Remi Weber, K. Patricia Hartmann, Merel van Gogh, Dominik Brücher, Heinz Läubli, Andreas Plückthun

{"title":"DARPin-fused T cell engager for adenovirus-mediated cancer therapy","authors":"Patrick C. Freitag, Jonas Kolibius, Ronja Wieboldt, Remi Weber, K. Patricia Hartmann, Merel van Gogh, Dominik Brücher, Heinz Läubli, Andreas Plückthun","doi":"10.1016/j.omton.2024.200821","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200821","url":null,"abstract":"Bispecific T cell engagers are a promising class of therapeutic proteins for cancer therapy. Their potency and small size often come with systemic toxicity and short half-life, making intravenous administration cumbersome. These limitations can be overcome by tumor-specific expression, allowing high local accumulation while reducing systemic concentrations. However, encoding T cell engagers in viral or non-viral vectors and expressing them ablates all forms of quality control performed during recombinant protein production. It is therefore vital to design constructs that feature minimal domain mispairing, and increased homogeneity of the therapeutic product. Here, we report a T cell engager architecture specifically designed for vector-mediated immunotherapy. It is based on a fusion of a designed ankyrin repeat protein (DARPin) to a CD3-targeting single-chain antibody fragment, termed DATE (RPin-fused cell ngager). The DATE induces potent T cell-mediated killing of HER2 cancer cells, both as recombinantly produced therapeutic protein and as expressed payload from a HER2-retargeted high-capacity adenoviral vector (HC-AdV). We report remarkable tumor remission, DATE accumulation, and T cell infiltration through expression mediated by a HER2-retargeted HC-AdV . Our results support further investigations and developments of DATEs as payloads for vector-mediated immunotherapy.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141531509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancing antitumor efficacy of oncolytic virus M1 via albendazole-sustained CD8+T cell activation 通过阿苯达唑维持的 CD8+T 细胞激活增强溶瘤病毒 M1 的抗肿瘤功效

Molecular Therapy: Oncology Pub Date : 2024-05-06 DOI: 10.1016/j.omton.2024.200813

Wenjing Bai, Xia Tang, Tong Xiao, Yangyang Qiao, Xuyan Tian, Bo Zhu, Jiehong Chen, ChaoXin Chen, Yuanyuan Li, Xueying Lin, Jing Cai, Yuan Lin, Wenbo Zhu, Guangmei Yan, Jiankai Liang, Jun Hu

{"title":"Enhancing antitumor efficacy of oncolytic virus M1 via albendazole-sustained CD8+T cell activation","authors":"Wenjing Bai, Xia Tang, Tong Xiao, Yangyang Qiao, Xuyan Tian, Bo Zhu, Jiehong Chen, ChaoXin Chen, Yuanyuan Li, Xueying Lin, Jing Cai, Yuan Lin, Wenbo Zhu, Guangmei Yan, Jiankai Liang, Jun Hu","doi":"10.1016/j.omton.2024.200813","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200813","url":null,"abstract":"The immune response plays a crucial role in the functionality of oncolytic viruses. In this study, Albendazole, an antihelminthic drug known to modulate the immune checkpoint PD-L1, was combined with the oncolytic virus M1 (OVM1) to treat mice with either prostate cancer (RM-1) or glioma (GL261) tumors. This combination therapy enhanced anti-tumor effects in immunocompetent mice, but not in immunodeficient ones, without increasing OVM1 replication. Instead, it led to an increase in the number of CD8+T cells within the tumor, downregulated the expression of PD1 on CD8+T cells, and upregulated activation markers such as Ki67, CD44, and CD69 and the secretion of cytotoxic factors including interferon (IFN)-γ, granzyme B, and tumor necrosis factor (TNF)-α. Consistently, it enhanced the tumor-killing activity of lymphocytes from tumor-draining lymph nodes or spleens. The synergistic effect of Albendazole on OVM1 was abolished by depleting CD8+ T cells, suggesting a CD8+ T cell-dependent mechanism. In addition, Albendazole and OVM1 therapy increased CTLA4 expression in the spleen, and the addition of CTLA4 antibodies further enhanced the anti-tumor efficacy . In summary, Albendazole can act synergistically with oncolytic viruses via CD8+T cell activation, and the Albendazole/OVM1 combination can overcome resistance to CTLA4-based immune checkpoint blockade therapy.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"106 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140942589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intra-tumoral administration of CHST15 siRNA remodels tumoral stroma and tumor-draining lymph nodes and augments tumor-infiltrating T cells in pancreatic cancer in mice 瘤内给药 CHST15 siRNA 可重塑肿瘤基质和肿瘤引流淋巴结，并增强小鼠胰腺癌的肿瘤浸润 T 细胞

Molecular Therapy: Oncology Pub Date : 2024-05-03 DOI: 10.1016/j.omton.2024.200812

Juanjuan Ye, Futoshi Suizu, Keiko Yamakawa, Yuri Mukai, Hiroyuki Yoneyama, Jiro Kondo, Motohiko Kato, Akira Nishiyama, Naohisa Yahagi, Kyuichi Kadota

{"title":"Intra-tumoral administration of CHST15 siRNA remodels tumoral stroma and tumor-draining lymph nodes and augments tumor-infiltrating T cells in pancreatic cancer in mice","authors":"Juanjuan Ye, Futoshi Suizu, Keiko Yamakawa, Yuri Mukai, Hiroyuki Yoneyama, Jiro Kondo, Motohiko Kato, Akira Nishiyama, Naohisa Yahagi, Kyuichi Kadota","doi":"10.1016/j.omton.2024.200812","DOIUrl":"https://doi.org/10.1016/j.omton.2024.200812","url":null,"abstract":"The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph nodes (TDLNs), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G MDSCs . Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. , CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33 MDSCs derived from human peripheral blood mononuclear cells. These results suggest a dual role for intra-tumorally injected CHST15 siRNA on modulating the tumor immune microenvironment for T cell entry and remotely diminishing CHST15 MDSCs, decreasing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs.","PeriodicalId":519910,"journal":{"name":"Molecular Therapy: Oncology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140942588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Emerging delivery strategy for oncolytic virotherapy 溶瘤病毒疗法的新兴传输策略

Molecular Therapy: Oncology Pub Date : 2024-04-29 DOI: 10.1016/j.omton.2024.200809

Jiao Zhu, Jinhu Ma, Meijuan Huang, Hongxin Deng, Gang Shi

引用次数: 0