Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma
Abstract Immunomodulatory agent lenalidomide is effective in treating follicular lymphoma (FL). We conducted the first trial of immunotherapy rituximab plus lenalidomide in newly diagnosed FL in China (NCT03715309). One-hundred and fifteen patients were enrolled and treated with rituximab 375 mg/m2...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-024-02105-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585369213730816 |
|---|---|
| author | Zhong Zheng Jian-Biao Wang Rui Sun Nan Wang Xiang-Qin Weng Tian-Yuan Xu Di Fu Yan Feng Peng-Peng Xu Shu Cheng Li Wang Yan Zhao Bin Qu Chuan-Xin Huang Wei-Li Zhao |
| author_facet | Zhong Zheng Jian-Biao Wang Rui Sun Nan Wang Xiang-Qin Weng Tian-Yuan Xu Di Fu Yan Feng Peng-Peng Xu Shu Cheng Li Wang Yan Zhao Bin Qu Chuan-Xin Huang Wei-Li Zhao |
| author_sort | Zhong Zheng |
| collection | DOAJ |
| description | Abstract Immunomodulatory agent lenalidomide is effective in treating follicular lymphoma (FL). We conducted the first trial of immunotherapy rituximab plus lenalidomide in newly diagnosed FL in China (NCT03715309). One-hundred and fifteen patients were enrolled and treated with rituximab 375 mg/m2 intravenously on day 0 and lenalidomide 25 mg orally on day 1–10 for 6 cycles of induction treatment, as well as lenalidomide for 6 cycles and rituximab for 8 cycles of maintenance treatment. We found that inferior progression-free survival of the patients was significantly associated with elevated serum β2m and lymph node >6 cm, linking to decreased lymphoma cell autophagy and dendritic cell infiltration within the tumor microenvironment. PU.1 transcriptionally downregulated PD-L1 (Programmed death ligand 1) expression and upregulated 4-1BBL (4-1BB ligand) expression, increased lymphoma cell autophagy and dendritic cell maturation via PD-1/PD-L1 and 4-1BB/4-1BBL interaction. In vitro in co-culture system and in vivo in murine xenograft model, knockdown of PU.1 induced lenalidomide resistance, but sensitized FL cells to bi-specific PD-L1/4-1BB antibody or combined treatment of PD-L1 inhibitor and 4-1BB agonist. Collectively, PU.1 is essential in immunomodulatory effect of FL through PD-1/PD-L1- and 4-1BB/4-1BBL-mediated microenvironmental modulation. Dual targeting PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in the chemo-free era of FL treatment. |
| format | Article |
| id | doaj-art-8ed9fce2afcf4d1a8a24ad2139fa84be |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-8ed9fce2afcf4d1a8a24ad2139fa84be2025-01-26T12:54:32ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-01-0110111310.1038/s41392-024-02105-7Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphomaZhong Zheng0Jian-Biao Wang1Rui Sun2Nan Wang3Xiang-Qin Weng4Tian-Yuan Xu5Di Fu6Yan Feng7Peng-Peng Xu8Shu Cheng9Li Wang10Yan Zhao11Bin Qu12Chuan-Xin Huang13Wei-Li Zhao14Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineDepartment of Laboratory Medicine, Shanghai RuiJin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineState Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineDepartment of Laboratory Medicine, Shanghai RuiJin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Immunobiology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineAbstract Immunomodulatory agent lenalidomide is effective in treating follicular lymphoma (FL). We conducted the first trial of immunotherapy rituximab plus lenalidomide in newly diagnosed FL in China (NCT03715309). One-hundred and fifteen patients were enrolled and treated with rituximab 375 mg/m2 intravenously on day 0 and lenalidomide 25 mg orally on day 1–10 for 6 cycles of induction treatment, as well as lenalidomide for 6 cycles and rituximab for 8 cycles of maintenance treatment. We found that inferior progression-free survival of the patients was significantly associated with elevated serum β2m and lymph node >6 cm, linking to decreased lymphoma cell autophagy and dendritic cell infiltration within the tumor microenvironment. PU.1 transcriptionally downregulated PD-L1 (Programmed death ligand 1) expression and upregulated 4-1BBL (4-1BB ligand) expression, increased lymphoma cell autophagy and dendritic cell maturation via PD-1/PD-L1 and 4-1BB/4-1BBL interaction. In vitro in co-culture system and in vivo in murine xenograft model, knockdown of PU.1 induced lenalidomide resistance, but sensitized FL cells to bi-specific PD-L1/4-1BB antibody or combined treatment of PD-L1 inhibitor and 4-1BB agonist. Collectively, PU.1 is essential in immunomodulatory effect of FL through PD-1/PD-L1- and 4-1BB/4-1BBL-mediated microenvironmental modulation. Dual targeting PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in the chemo-free era of FL treatment.https://doi.org/10.1038/s41392-024-02105-7 |
| spellingShingle | Zhong Zheng Jian-Biao Wang Rui Sun Nan Wang Xiang-Qin Weng Tian-Yuan Xu Di Fu Yan Feng Peng-Peng Xu Shu Cheng Li Wang Yan Zhao Bin Qu Chuan-Xin Huang Wei-Li Zhao Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma Signal Transduction and Targeted Therapy |
| title | Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma |
| title_full | Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma |
| title_fullStr | Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma |
| title_full_unstemmed | Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma |
| title_short | Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma |
| title_sort | dual targeting pd l1 and 4 1bb to overcome dendritic cell mediated lenalidomide resistance in follicular lymphoma |
| url | https://doi.org/10.1038/s41392-024-02105-7 |
| work_keys_str_mv | AT zhongzheng dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT jianbiaowang dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT ruisun dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT nanwang dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT xiangqinweng dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT tianyuanxu dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT difu dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT yanfeng dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT pengpengxu dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT shucheng dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT liwang dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT yanzhao dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT binqu dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT chuanxinhuang dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma AT weilizhao dualtargetingpdl1and41bbtoovercomedendriticcellmediatedlenalidomideresistanceinfollicularlymphoma |