GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer
Pancreatic cancer is one of the most aggressive cancers and poses significant challenges to current therapies because of its complex immunosuppressive tumor microenvironment (TME). Oncolytic viruses armed with immunoregulatory molecules are promising strategies to overcome limited efficacy and targe...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1506632/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841561070267793408 |
|---|---|
| author | Yujing Xuan Wenyi Yan Ruimin Wang Xibin Wang Yu Guo Huilin Dun Ziyan Huan Lihua Xu Ruxia Han Xianlei Sun Lingling Si Nicholas R. Lemoine Nicholas R. Lemoine Yaohe Wang Yaohe Wang Pengju Wang |
| author_facet | Yujing Xuan Wenyi Yan Ruimin Wang Xibin Wang Yu Guo Huilin Dun Ziyan Huan Lihua Xu Ruxia Han Xianlei Sun Lingling Si Nicholas R. Lemoine Nicholas R. Lemoine Yaohe Wang Yaohe Wang Pengju Wang |
| author_sort | Yujing Xuan |
| collection | DOAJ |
| description | Pancreatic cancer is one of the most aggressive cancers and poses significant challenges to current therapies because of its complex immunosuppressive tumor microenvironment (TME). Oncolytic viruses armed with immunoregulatory molecules are promising strategies to overcome limited efficacy and target inaccessible and metastatic tumors. In this study, we constructed a tumor-selective vaccinia virus (VV) with deletions of the TK and A49 genes (VVLΔTKΔA49, VVL-DD) using CRISPR-Cas9-based homologous recombination. VVL-DD exhibited significant tumor selectivity in vitro and anti-tumor potency in vivo in a murine pancreatic cancer model. Then, VVL-DD was armed with an optimal combination of immunomodulatory molecules, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-21 (IL-21), to produce VVL-GL21. VVL-GL21 induced significant tumor regression after intratumoral and systemic administration. Moreover, VVL-GL21 increased the infiltration of dendritic cells (DCs), macrophages, and T cells; induced DC maturation; increased the transition from M2 to M1 macrophages; improved the formation of immune memory; prevented tumor recurrence; and effectively bolstered the immune response against tumors in multiple key immune compartments. Interestingly, mice bearing-pancreatic cancer tumors treated with VVL-GL21 showed anti-tumor immunity against lung and colon cancer tumors. Importantly, treatment with VVL-GL21 enhanced the responsiveness of tumors to the immune checkpoint inhibitor anti-PD1. Taken together, VVL-GL21 remodels the suppressive TME and has powerful anti-tumor activities as monotherapy or in combination with anti-PD1 by intratumoral or systemic delivery for the treatment of pancreatic cancer. VVL-GL21 could be used as a therapeutic cancer vaccine. |
| format | Article |
| id | doaj-art-dd382cebc04042b887e18f1ae1f7da61 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-dd382cebc04042b887e18f1ae1f7da612025-01-03T06:47:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15066321506632GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancerYujing Xuan0Wenyi Yan1Ruimin Wang2Xibin Wang3Yu Guo4Huilin Dun5Ziyan Huan6Lihua Xu7Ruxia Han8Xianlei Sun9Lingling Si10Nicholas R. Lemoine11Nicholas R. Lemoine12Yaohe Wang13Yaohe Wang14Pengju Wang15Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaDepartment of Pathology, Zhengzhou People’s Hospital, Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaCentre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaCentre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaPancreatic cancer is one of the most aggressive cancers and poses significant challenges to current therapies because of its complex immunosuppressive tumor microenvironment (TME). Oncolytic viruses armed with immunoregulatory molecules are promising strategies to overcome limited efficacy and target inaccessible and metastatic tumors. In this study, we constructed a tumor-selective vaccinia virus (VV) with deletions of the TK and A49 genes (VVLΔTKΔA49, VVL-DD) using CRISPR-Cas9-based homologous recombination. VVL-DD exhibited significant tumor selectivity in vitro and anti-tumor potency in vivo in a murine pancreatic cancer model. Then, VVL-DD was armed with an optimal combination of immunomodulatory molecules, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-21 (IL-21), to produce VVL-GL21. VVL-GL21 induced significant tumor regression after intratumoral and systemic administration. Moreover, VVL-GL21 increased the infiltration of dendritic cells (DCs), macrophages, and T cells; induced DC maturation; increased the transition from M2 to M1 macrophages; improved the formation of immune memory; prevented tumor recurrence; and effectively bolstered the immune response against tumors in multiple key immune compartments. Interestingly, mice bearing-pancreatic cancer tumors treated with VVL-GL21 showed anti-tumor immunity against lung and colon cancer tumors. Importantly, treatment with VVL-GL21 enhanced the responsiveness of tumors to the immune checkpoint inhibitor anti-PD1. Taken together, VVL-GL21 remodels the suppressive TME and has powerful anti-tumor activities as monotherapy or in combination with anti-PD1 by intratumoral or systemic delivery for the treatment of pancreatic cancer. VVL-GL21 could be used as a therapeutic cancer vaccine.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1506632/fulloncolytic vaccinia virusGM-CSFIL-21pancreatic canceranti-PD1 |
| spellingShingle | Yujing Xuan Wenyi Yan Ruimin Wang Xibin Wang Yu Guo Huilin Dun Ziyan Huan Lihua Xu Ruxia Han Xianlei Sun Lingling Si Nicholas R. Lemoine Nicholas R. Lemoine Yaohe Wang Yaohe Wang Pengju Wang GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer Frontiers in Immunology oncolytic vaccinia virus GM-CSF IL-21 pancreatic cancer anti-PD1 |
| title | GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer |
| title_full | GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer |
| title_fullStr | GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer |
| title_full_unstemmed | GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer |
| title_short | GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer |
| title_sort | gm csf and il 21 armed oncolytic vaccinia virus significantly enhances anti tumor activity and synergizes with anti pd1 immunotherapy in pancreatic cancer |
| topic | oncolytic vaccinia virus GM-CSF IL-21 pancreatic cancer anti-PD1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1506632/full |
| work_keys_str_mv | AT yujingxuan gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT wenyiyan gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT ruiminwang gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT xibinwang gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT yuguo gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT huilindun gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT ziyanhuan gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT lihuaxu gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT ruxiahan gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT xianleisun gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT linglingsi gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT nicholasrlemoine gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT nicholasrlemoine gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT yaohewang gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT yaohewang gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer AT pengjuwang gmcsfandil21armedoncolyticvacciniavirussignificantlyenhancesantitumoractivityandsynergizeswithantipd1immunotherapyinpancreaticcancer |