CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma
Abstract Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Her...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55876-0 |
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| author | Jiaojiao Xu Zhe Li Qinli Tong Sihang Zhang Jianchen Fang Aihua Wu Guoguang Wei Chen Zhang Sheng Yu Binbin Zheng Hongzheng Lin Xueling Liao Zeyu Xiao Wei Lu |
| author_facet | Jiaojiao Xu Zhe Li Qinli Tong Sihang Zhang Jianchen Fang Aihua Wu Guoguang Wei Chen Zhang Sheng Yu Binbin Zheng Hongzheng Lin Xueling Liao Zeyu Xiao Wei Lu |
| author_sort | Jiaojiao Xu |
| collection | DOAJ |
| description | Abstract Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages. Compared to the CD133-PD-L1- cancer cells, the CD133+PD-L1+ cancer cells express higher transforming growth factor-β signaling molecules to foster a resistant tumor niche, that restricts the trafficking of the transferred macrophages by stiffened extracellular matrix, and inhibits their cell-killing capability by immunosuppressive factors. The CD133+PD-L1+ cancer cells exhibit tumorigenic potential. The CD133+PD-L1+ cells are further identified in the clinically metastatic melanoma. Hyperthermia reverses the resistance of CD133+PD-L1+ cancer cells through upregulating the ‘eat me’ signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy. Our findings demonstrate the mechanism of resistance to adoptive macrophage therapy, and provide a de novo strategy to counteract the resistance. |
| format | Article |
| id | doaj-art-eeb5cab1ff4b45939fada69b808fef6f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-eeb5cab1ff4b45939fada69b808fef6f2025-01-26T12:40:36ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-025-55876-0CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanomaJiaojiao Xu0Zhe Li1Qinli Tong2Sihang Zhang3Jianchen Fang4Aihua Wu5Guoguang Wei6Chen Zhang7Sheng Yu8Binbin Zheng9Hongzheng Lin10Xueling Liao11Zeyu Xiao12Wei Lu13School of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversityDepartment of Pathology, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, Shanghai Jiao Tong University School of MedicineSchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversitySchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversityDepartment of Pathology, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, Shanghai Jiao Tong University School of MedicineSchool of Pharmacy, Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Molecular Engineering of Polymers, Fudan UniversityAbstract Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages. Compared to the CD133-PD-L1- cancer cells, the CD133+PD-L1+ cancer cells express higher transforming growth factor-β signaling molecules to foster a resistant tumor niche, that restricts the trafficking of the transferred macrophages by stiffened extracellular matrix, and inhibits their cell-killing capability by immunosuppressive factors. The CD133+PD-L1+ cancer cells exhibit tumorigenic potential. The CD133+PD-L1+ cells are further identified in the clinically metastatic melanoma. Hyperthermia reverses the resistance of CD133+PD-L1+ cancer cells through upregulating the ‘eat me’ signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy. Our findings demonstrate the mechanism of resistance to adoptive macrophage therapy, and provide a de novo strategy to counteract the resistance.https://doi.org/10.1038/s41467-025-55876-0 |
| spellingShingle | Jiaojiao Xu Zhe Li Qinli Tong Sihang Zhang Jianchen Fang Aihua Wu Guoguang Wei Chen Zhang Sheng Yu Binbin Zheng Hongzheng Lin Xueling Liao Zeyu Xiao Wei Lu CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma Nature Communications |
| title | CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma |
| title_full | CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma |
| title_fullStr | CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma |
| title_full_unstemmed | CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma |
| title_short | CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma |
| title_sort | cd133 pd l1 cancer cells confer resistance to adoptively transferred engineered macrophage based therapy in melanoma |
| url | https://doi.org/10.1038/s41467-025-55876-0 |
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