PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer
Abstract Background Programmed cell death ligand 1 (PD-L1) expression on immune cells is correlated with the efficacy of immune checkpoint inhibitor (ICI) therapy in various types of cancer. Platelets are important components of the tumour microenvironment (TME) and are widely involved in the develo...
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BMC
2025-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02034-0 |
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| author | Jiacheng Li Jia Liu Shifeng Yang Yu Xia Qingzhe Meng Biying Sun Yansong Liu Bin Zhao Jiaqi Jin Hui Xu Lihong Wang Pengxia Zhang Zhuoxin Cheng |
| author_facet | Jiacheng Li Jia Liu Shifeng Yang Yu Xia Qingzhe Meng Biying Sun Yansong Liu Bin Zhao Jiaqi Jin Hui Xu Lihong Wang Pengxia Zhang Zhuoxin Cheng |
| author_sort | Jiacheng Li |
| collection | DOAJ |
| description | Abstract Background Programmed cell death ligand 1 (PD-L1) expression on immune cells is correlated with the efficacy of immune checkpoint inhibitor (ICI) therapy in various types of cancer. Platelets are important components of the tumour microenvironment (TME) and are widely involved in the development of many types of cancer including colorectal cancer (CRC). However, the role of PD-L1 positive platelets in ICI therapy for CRC remains unknown. We hypothesized that PD-L1 positive platelets trigger and sustain CRC immunosuppression. Methods The functional depletion effects of PD-L1 positive platelets on TME and immune cells were measured via western blotting, immunofluorescence staining, qRT-PCR, ELISpot and flow cytometry. In vivo, CD274 knockout (KO), CD8a KO, platelet-specific KO (PF4-Cre-Hsp90b1flox/flox) mouse models and a subcutaneous tumour model treated with aspirin and PD-L1 mAb were established in C57BL/6 N mice. Results We found that PD-L1 positive platelets are correlated with a poor prognosis, CD8 + T cell exhaustion and serve as a novel noninvasive biomarker for predicting immunotherapy efficacy in patients with CRC. The transfer of PD-L1 from tumour cells to platelets in the TME depends on direct cell contact via the fibronectin-1/GPIbα/integrin α5β1 pathway. In turn, platelets can also induce PD-L1 expression on cancer cells. Animal experiments revealed that antiplatelet pharmacological agents and genetic knockout of platelets potentiated the antitumour effect of the PD-L1 mAb treatment in a CD8 + T cell dependent manner. Conclusions Our data suggest that PD-L1 positive platelets suppress CD8 + T cell immunity. Clinical combination treatment with ICIs and antiplatelet agents may be an effective therapeutic strategy for treating CRC. |
| format | Article |
| id | doaj-art-dd2715720ccd435d84de27f40e99565b |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-dd2715720ccd435d84de27f40e99565b2025-01-19T12:33:06ZengBMCCell Communication and Signaling1478-811X2025-01-0123111710.1186/s12964-025-02034-0PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancerJiacheng Li0Jia Liu1Shifeng Yang2Yu Xia3Qingzhe Meng4Biying Sun5Yansong Liu6Bin Zhao7Jiaqi Jin8Hui Xu9Lihong Wang10Pengxia Zhang11Zhuoxin Cheng12Digestive Disease Center, The First Affiliated Hospital of Jiamusi UniversityKey Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi UniversityDepartment of General Surgery, The Second Affiliated Hospital of Harbin Medical UniversityDigestive Disease Center, The First Affiliated Hospital of Jiamusi UniversityDigestive Disease Center, The First Affiliated Hospital of Jiamusi UniversityDigestive Disease Center, The First Affiliated Hospital of Jiamusi UniversityDigestive Disease Center, The First Affiliated Hospital of Jiamusi UniversityDigestive Disease Center, The First Affiliated Hospital of Jiamusi UniversityDepartment of Neurosurgery, Xuanwu Hospital, Capital Medical UniversityKey Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi UniversityCollege of Pharmacy, Jiamusi UniversityKey Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi UniversityDigestive Disease Center, The First Affiliated Hospital of Jiamusi UniversityAbstract Background Programmed cell death ligand 1 (PD-L1) expression on immune cells is correlated with the efficacy of immune checkpoint inhibitor (ICI) therapy in various types of cancer. Platelets are important components of the tumour microenvironment (TME) and are widely involved in the development of many types of cancer including colorectal cancer (CRC). However, the role of PD-L1 positive platelets in ICI therapy for CRC remains unknown. We hypothesized that PD-L1 positive platelets trigger and sustain CRC immunosuppression. Methods The functional depletion effects of PD-L1 positive platelets on TME and immune cells were measured via western blotting, immunofluorescence staining, qRT-PCR, ELISpot and flow cytometry. In vivo, CD274 knockout (KO), CD8a KO, platelet-specific KO (PF4-Cre-Hsp90b1flox/flox) mouse models and a subcutaneous tumour model treated with aspirin and PD-L1 mAb were established in C57BL/6 N mice. Results We found that PD-L1 positive platelets are correlated with a poor prognosis, CD8 + T cell exhaustion and serve as a novel noninvasive biomarker for predicting immunotherapy efficacy in patients with CRC. The transfer of PD-L1 from tumour cells to platelets in the TME depends on direct cell contact via the fibronectin-1/GPIbα/integrin α5β1 pathway. In turn, platelets can also induce PD-L1 expression on cancer cells. Animal experiments revealed that antiplatelet pharmacological agents and genetic knockout of platelets potentiated the antitumour effect of the PD-L1 mAb treatment in a CD8 + T cell dependent manner. Conclusions Our data suggest that PD-L1 positive platelets suppress CD8 + T cell immunity. Clinical combination treatment with ICIs and antiplatelet agents may be an effective therapeutic strategy for treating CRC.https://doi.org/10.1186/s12964-025-02034-0PD-L1PlateletColorectal cancerImmune checkpoint inhibitors |
| spellingShingle | Jiacheng Li Jia Liu Shifeng Yang Yu Xia Qingzhe Meng Biying Sun Yansong Liu Bin Zhao Jiaqi Jin Hui Xu Lihong Wang Pengxia Zhang Zhuoxin Cheng PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer Cell Communication and Signaling PD-L1 Platelet Colorectal cancer Immune checkpoint inhibitors |
| title | PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer |
| title_full | PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer |
| title_fullStr | PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer |
| title_full_unstemmed | PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer |
| title_short | PD-L1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer |
| title_sort | pd l1 positive platelets mediate resistance to immune checkpoint inhibitors in patients with colorectal cancer |
| topic | PD-L1 Platelet Colorectal cancer Immune checkpoint inhibitors |
| url | https://doi.org/10.1186/s12964-025-02034-0 |
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