The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy
In the era of immune checkpoint blockade cancer therapy, cytokines have become an attractive immune therapeutics to increase response rates. Interleukin 21 (IL21) as a single agent has been evaluated for cancer treatment with good clinical efficacy. However, the clinical application of IL21 is limit...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.779865/full |
| _version_ | 1818569071535325184 |
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| author | Shaoxian Wu Shaoxian Wu Runzi Sun Runzi Sun Bo Tan Bendong Chen Wenyan Zhou David Shihong Gao Joshua Zhong Hao Huang Jingting Jiang Binfeng Lu |
| author_facet | Shaoxian Wu Shaoxian Wu Runzi Sun Runzi Sun Bo Tan Bendong Chen Wenyan Zhou David Shihong Gao Joshua Zhong Hao Huang Jingting Jiang Binfeng Lu |
| author_sort | Shaoxian Wu |
| collection | DOAJ |
| description | In the era of immune checkpoint blockade cancer therapy, cytokines have become an attractive immune therapeutics to increase response rates. Interleukin 21 (IL21) as a single agent has been evaluated for cancer treatment with good clinical efficacy. However, the clinical application of IL21 is limited by a short half-life and concern about potential immune suppressive effect on dendritic cells. Here, we examined the antitumor function of a half-life extended IL21 alone and in combination with PD-1 blockade using preclinical mouse tumor models. We also determined the immune mechanisms of combination therapy. We found that combination therapy additively inhibited the growth of mouse tumors by increasing the effector function of type 1 lymphocytes. Combination therapy also increased the fraction of type 1 dendritic cells (DC1s) and M1 macrophages in the tumor microenvironment (TME). However, combination therapy also induced immune regulatory mechanisms, including the checkpoint molecules Tim-3, Lag-3, and CD39, as well as myeloid derived suppressor cells (MDSC). This study reveals the mechanisms of IL21/PD-1 cooperation and shed light on rational design of novel combination cancer immunotherapy. |
| first_indexed | 2024-12-14T06:43:14Z |
| format | Article |
| id | doaj.art-fe289798c870401186124d0b6697ca1d |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-14T06:43:14Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-fe289798c870401186124d0b6697ca1d2022-12-21T23:13:09ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-11-01910.3389/fcell.2021.779865779865The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor ImmunotherapyShaoxian Wu0Shaoxian Wu1Runzi Sun2Runzi Sun3Bo Tan4Bendong Chen5Wenyan Zhou6David Shihong Gao7Joshua Zhong8Hao Huang9Jingting Jiang10Binfeng Lu11Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, ChinaDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, ChinaDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, ChinaDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, ChinaDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, ChinaDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesIn the era of immune checkpoint blockade cancer therapy, cytokines have become an attractive immune therapeutics to increase response rates. Interleukin 21 (IL21) as a single agent has been evaluated for cancer treatment with good clinical efficacy. However, the clinical application of IL21 is limited by a short half-life and concern about potential immune suppressive effect on dendritic cells. Here, we examined the antitumor function of a half-life extended IL21 alone and in combination with PD-1 blockade using preclinical mouse tumor models. We also determined the immune mechanisms of combination therapy. We found that combination therapy additively inhibited the growth of mouse tumors by increasing the effector function of type 1 lymphocytes. Combination therapy also increased the fraction of type 1 dendritic cells (DC1s) and M1 macrophages in the tumor microenvironment (TME). However, combination therapy also induced immune regulatory mechanisms, including the checkpoint molecules Tim-3, Lag-3, and CD39, as well as myeloid derived suppressor cells (MDSC). This study reveals the mechanisms of IL21/PD-1 cooperation and shed light on rational design of novel combination cancer immunotherapy.https://www.frontiersin.org/articles/10.3389/fcell.2021.779865/fullinterleukin 21checkpoint inhibitorstumor microenvironmentimmunotherapymechanisms |
| spellingShingle | Shaoxian Wu Shaoxian Wu Runzi Sun Runzi Sun Bo Tan Bendong Chen Wenyan Zhou David Shihong Gao Joshua Zhong Hao Huang Jingting Jiang Binfeng Lu The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy Frontiers in Cell and Developmental Biology interleukin 21 checkpoint inhibitors tumor microenvironment immunotherapy mechanisms |
| title | The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy |
| title_full | The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy |
| title_fullStr | The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy |
| title_full_unstemmed | The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy |
| title_short | The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy |
| title_sort | half life extended il21 can be combined with multiple checkpoint inhibitors for tumor immunotherapy |
| topic | interleukin 21 checkpoint inhibitors tumor microenvironment immunotherapy mechanisms |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.779865/full |
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