Zhongjie Yu, Zhen Guo, Bin Jiang, Yueshu Zhu, Lin Shao, Xinhua Zhang, Yi Zhao, Di Wu, Aotian Xu
{"title":"IL-7-PD-L1纳米抗体介导的“拉链”效应增强了肿瘤浸润淋巴细胞的杀肿瘤活性。","authors":"Zhongjie Yu, Zhen Guo, Bin Jiang, Yueshu Zhu, Lin Shao, Xinhua Zhang, Yi Zhao, Di Wu, Aotian Xu","doi":"10.1186/s40164-025-00702-y","DOIUrl":null,"url":null,"abstract":"<p><p>Cancer represents a pressing global health concern, characterized by a substantial number of unmet clinical needs. Cell therapy has emerged as a promising and efficacious approach for cancer treatment, particularly tumor-infiltrating lymphocytes (TILs), which have demonstrated remarkable improvements in patients' overall survival rates across various clinical studies. However, the tumor microenvironment exerts a adverse effect on TILs, leading to their rapid exhaustion and functional disorder. Consequently, this impedes their ability to effectively eradicate tumors and thus hinders the achievement of the anticipated therapeutic efficacy. Here, we employed lentiviral vector-mediated genetic engineering to manipulate TILs for the expression of TIGIT shRNA, IL-7-PD-L1 nano-antibody fusion protein, and the 'molecular switch' HuEGFRt. The engineered TILs exhibited higher viability, reinforced cell expansion, and reduced reliance on IL-2. The stem-like proportion of engineered TILs is significantly augmented, and their activation level is enhanced when co-cultured with tumor cells. Meanwhile, the engineered TILs exert sustained cytotoxicity after repeated stimulation from tumor cells. The use of Cetuximab has been demonstrated in vitro to induce specific apoptosis of engineered TILs through HuEGFRt, thereby ensuring safety throughout the treatment process. In the mouse tumor model, following infusion of engineered TILs, the tumor volume significantly reduced, once again demonstrating the effectiveness of engineered TILs. The findings of our study demonstrate the exceptional performance of engineered TILs, which undoubtedly holds great promise for the clinical application of engineered TILs, ultimately benefiting a larger population of cancer patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"112"},"PeriodicalIF":13.5000,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398053/pdf/","citationCount":"0","resultStr":"{\"title\":\"IL-7-PD-L1 nano-antibody mediated \\\"zipper\\\" effect augments the tumoricidal activity of tumor-infiltrating lymphocytes.\",\"authors\":\"Zhongjie Yu, Zhen Guo, Bin Jiang, Yueshu Zhu, Lin Shao, Xinhua Zhang, Yi Zhao, Di Wu, Aotian Xu\",\"doi\":\"10.1186/s40164-025-00702-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Cancer represents a pressing global health concern, characterized by a substantial number of unmet clinical needs. Cell therapy has emerged as a promising and efficacious approach for cancer treatment, particularly tumor-infiltrating lymphocytes (TILs), which have demonstrated remarkable improvements in patients' overall survival rates across various clinical studies. However, the tumor microenvironment exerts a adverse effect on TILs, leading to their rapid exhaustion and functional disorder. Consequently, this impedes their ability to effectively eradicate tumors and thus hinders the achievement of the anticipated therapeutic efficacy. Here, we employed lentiviral vector-mediated genetic engineering to manipulate TILs for the expression of TIGIT shRNA, IL-7-PD-L1 nano-antibody fusion protein, and the 'molecular switch' HuEGFRt. The engineered TILs exhibited higher viability, reinforced cell expansion, and reduced reliance on IL-2. The stem-like proportion of engineered TILs is significantly augmented, and their activation level is enhanced when co-cultured with tumor cells. Meanwhile, the engineered TILs exert sustained cytotoxicity after repeated stimulation from tumor cells. The use of Cetuximab has been demonstrated in vitro to induce specific apoptosis of engineered TILs through HuEGFRt, thereby ensuring safety throughout the treatment process. In the mouse tumor model, following infusion of engineered TILs, the tumor volume significantly reduced, once again demonstrating the effectiveness of engineered TILs. The findings of our study demonstrate the exceptional performance of engineered TILs, which undoubtedly holds great promise for the clinical application of engineered TILs, ultimately benefiting a larger population of cancer patients.</p>\",\"PeriodicalId\":12180,\"journal\":{\"name\":\"Experimental Hematology & Oncology\",\"volume\":\"14 1\",\"pages\":\"112\"},\"PeriodicalIF\":13.5000,\"publicationDate\":\"2025-08-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398053/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Hematology & Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s40164-025-00702-y\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00702-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
IL-7-PD-L1 nano-antibody mediated "zipper" effect augments the tumoricidal activity of tumor-infiltrating lymphocytes.
Cancer represents a pressing global health concern, characterized by a substantial number of unmet clinical needs. Cell therapy has emerged as a promising and efficacious approach for cancer treatment, particularly tumor-infiltrating lymphocytes (TILs), which have demonstrated remarkable improvements in patients' overall survival rates across various clinical studies. However, the tumor microenvironment exerts a adverse effect on TILs, leading to their rapid exhaustion and functional disorder. Consequently, this impedes their ability to effectively eradicate tumors and thus hinders the achievement of the anticipated therapeutic efficacy. Here, we employed lentiviral vector-mediated genetic engineering to manipulate TILs for the expression of TIGIT shRNA, IL-7-PD-L1 nano-antibody fusion protein, and the 'molecular switch' HuEGFRt. The engineered TILs exhibited higher viability, reinforced cell expansion, and reduced reliance on IL-2. The stem-like proportion of engineered TILs is significantly augmented, and their activation level is enhanced when co-cultured with tumor cells. Meanwhile, the engineered TILs exert sustained cytotoxicity after repeated stimulation from tumor cells. The use of Cetuximab has been demonstrated in vitro to induce specific apoptosis of engineered TILs through HuEGFRt, thereby ensuring safety throughout the treatment process. In the mouse tumor model, following infusion of engineered TILs, the tumor volume significantly reduced, once again demonstrating the effectiveness of engineered TILs. The findings of our study demonstrate the exceptional performance of engineered TILs, which undoubtedly holds great promise for the clinical application of engineered TILs, ultimately benefiting a larger population of cancer patients.
期刊介绍:
Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings.
Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.