Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma
The overall survival rate of patients with osteosarcoma has remained stagnant at 15–30% for several decades. Although immunotherapy has revolutionized the oncology field, largely attributed to the success of immune-checkpoint blockade, the durability and efficacy of anti-PD1 (programmed cell death p...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-08-01
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| Series: | Journal of Bone Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212137419300661 |
| _version_ | 1818096803050946560 |
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| author | Jingzhe Zhang Ye Li Shoujun Yang Lening Zhang Wenjun Wang |
| author_facet | Jingzhe Zhang Ye Li Shoujun Yang Lening Zhang Wenjun Wang |
| author_sort | Jingzhe Zhang |
| collection | DOAJ |
| description | The overall survival rate of patients with osteosarcoma has remained stagnant at 15–30% for several decades. Although immunotherapy has revolutionized the oncology field, largely attributed to the success of immune-checkpoint blockade, the durability and efficacy of anti-PD1 (programmed cell death protein 1) mAb vary across different malignancies. Among the major reasons for tumor resistance to this immune checkpoint therapy is the absence of tumor-infiltrating cytotoxic T lymphocytes. However, the presence of intratumor exhausted PD1hi T cells also contributes to insensitivity to anti-PD1 treatment. In this study, we established the osteosarcoma mouse tumor model resistant to anti-PD1 mAb that harbored PD1hi T cells. Furthermore, flow cytometry analysis of tumor infiltrating leukocytes after treatment was used as a screening platform to identify agents that could re-sensitize T cells to anti-PD1 mAb. Results showed that anti-CD40 mAb treatment converted PD1hi T cells to PD1lo T cells, reversing phenotypic T cell exhaustion and sensitizing anti-PD1 refractory tumors to respond to anti-PD1 mAb. Results also showed that intratumor Treg presented with a less activated and attenuated suppressive phenotype after anti-CD40 mAb treatment. Our study provides proof of concept to systematically identify immune conditioning agents, which are able to convert PD1hi T cells to PD1lo T cells, with clinical implications in the treatment against refractory osteosarcoma to anti-PD1 mAb. Keywords: Anti-CD40, PD1 blockade, Osteosarcoma, Immunotherapy |
| first_indexed | 2024-12-10T23:10:25Z |
| format | Article |
| id | doaj.art-9a6645d7ef0d4674adea82b32735626b |
| institution | Directory Open Access Journal |
| issn | 2212-1374 |
| language | English |
| last_indexed | 2024-12-10T23:10:25Z |
| publishDate | 2019-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Bone Oncology |
| spelling | doaj.art-9a6645d7ef0d4674adea82b32735626b2022-12-22T01:29:57ZengElsevierJournal of Bone Oncology2212-13742019-08-0117Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcomaJingzhe Zhang0Ye Li1Shoujun Yang2Lening Zhang3Wenjun Wang4Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of ChinaDepartment of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of ChinaDepartment of Physiatry, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of ChinaDepartment of Cardiothoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of ChinaDepartment of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China; Corresponding author.The overall survival rate of patients with osteosarcoma has remained stagnant at 15–30% for several decades. Although immunotherapy has revolutionized the oncology field, largely attributed to the success of immune-checkpoint blockade, the durability and efficacy of anti-PD1 (programmed cell death protein 1) mAb vary across different malignancies. Among the major reasons for tumor resistance to this immune checkpoint therapy is the absence of tumor-infiltrating cytotoxic T lymphocytes. However, the presence of intratumor exhausted PD1hi T cells also contributes to insensitivity to anti-PD1 treatment. In this study, we established the osteosarcoma mouse tumor model resistant to anti-PD1 mAb that harbored PD1hi T cells. Furthermore, flow cytometry analysis of tumor infiltrating leukocytes after treatment was used as a screening platform to identify agents that could re-sensitize T cells to anti-PD1 mAb. Results showed that anti-CD40 mAb treatment converted PD1hi T cells to PD1lo T cells, reversing phenotypic T cell exhaustion and sensitizing anti-PD1 refractory tumors to respond to anti-PD1 mAb. Results also showed that intratumor Treg presented with a less activated and attenuated suppressive phenotype after anti-CD40 mAb treatment. Our study provides proof of concept to systematically identify immune conditioning agents, which are able to convert PD1hi T cells to PD1lo T cells, with clinical implications in the treatment against refractory osteosarcoma to anti-PD1 mAb. Keywords: Anti-CD40, PD1 blockade, Osteosarcoma, Immunotherapyhttp://www.sciencedirect.com/science/article/pii/S2212137419300661 |
| spellingShingle | Jingzhe Zhang Ye Li Shoujun Yang Lening Zhang Wenjun Wang Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma Journal of Bone Oncology |
| title | Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma |
| title_full | Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma |
| title_fullStr | Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma |
| title_full_unstemmed | Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma |
| title_short | Anti-CD40 mAb enhanced efficacy of anti-PD1 against osteosarcoma |
| title_sort | anti cd40 mab enhanced efficacy of anti pd1 against osteosarcoma |
| url | http://www.sciencedirect.com/science/article/pii/S2212137419300661 |
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