Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockade
Abstract Background Immunotherapy is beneficial for some colorectal cancer (CRC) patients, but immunosuppressive networks limit its effectiveness. Cancer‐associatedfibroblasts (CAFs) are significant in immune escape and resistance toimmunotherapy, emphasizing the urgent need for new treatment strate...
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Wiley
2025-01-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70161 |
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| author | Shaoyong Peng Minshan Wu Qian Yan Gaopo Xu Yumo Xie Guannan Tang Jinxin Lin Zixu Yuan Xiaoxia Liang Ze Yuan Jingrong Weng Liangliang Bai Xiaolin Wang Huichuan Yu Meijin Huang Yanxin Luo Xiaoxia Liu |
| author_facet | Shaoyong Peng Minshan Wu Qian Yan Gaopo Xu Yumo Xie Guannan Tang Jinxin Lin Zixu Yuan Xiaoxia Liang Ze Yuan Jingrong Weng Liangliang Bai Xiaolin Wang Huichuan Yu Meijin Huang Yanxin Luo Xiaoxia Liu |
| author_sort | Shaoyong Peng |
| collection | DOAJ |
| description | Abstract Background Immunotherapy is beneficial for some colorectal cancer (CRC) patients, but immunosuppressive networks limit its effectiveness. Cancer‐associatedfibroblasts (CAFs) are significant in immune escape and resistance toimmunotherapy, emphasizing the urgent need for new treatment strategies. Methods Flow cytometric, Western blotting, proteomics analysis, analysis of public database data, genetically modified cell line models, T cell coculture, crystal violetstaining, ELISA, metabonomic and clinical tumour samples were conducted to assess the role of EDEM3 in immune escape and itsmolecular mechanisms. We evaluated theeffects of FMD plus 2‐DG on antitumour immunity using multipleximmunofluorescence, flow cytometry, cytokine profiling, TUNEL assays, xenografttumours, and in vivo studies. Results We show thatCAFs upregulate PD‐L1 glycosylation and contribute to immune evasion byglycosyltransferase EDEM3. Additionally, EDEM3 plays a role in tumour immunityduring tumour progression. However, the EDEM3‐mediated upregulation of PD‐L1 expression underpins PD‐1/PD‐L1 blockade resistance in vivo. This finding contradictsthe previous trend that positive PD‐L1 expression indicates a strong responseto PD‐1/PD‐L1 blockade. Mechanistically, high‐EDEM3 expression facilitates M2‐like This finding contradictsthe previous trend that positive PD‐L1 expression indicates a strong responseto PD‐1/PD‐L1 blockade.Mechanistically, polarizationand chemotactic migration of macrophages, which are enriched in theperipheral region of tumours compared to thecore region, precluding access of CD8+ T cells to tumourfoci. Furthermore, we EDEM3 predominantly activates the recruited M2‐like macrophagesvia a glucose metabolism‐dependent mechanism. Manipulationof glucose utilization by a fasting‐mimicking diet(FMD) plus 2‐DG treatmentsynergistically with PD‐1 antibody elicits potent antitumour activity byeffectively decreasing tumour glycosylated PD‐L1 expression, augmenting the CD8+effector T cell infiltration and activation while concurrently reducing the infiltration.TheCAFs‐EDEM3‐M2‐like macrophage axis plays a critical role in promotingimmunotherapy resistance. infiltration.TheCAFs‐EDEM3‐M2‐like macrophage axis plays a critical role in promotingimmunotherapy resistance. Conclusions Our study suggests that blocking EDEM3‐induced M2‐like macro phage trafficking by FMD plus 2‐DG is a promising and effective strategy to overcomeresistance to checkpoint blockade therapy offeringhope for improved treatment outcomes. Key points Cancer‐associated fibroblasts (CAFs) can enhance PD‐L1 glycosylation through the glycosyltransferase EDEM3, contributing to immune evasion during tumour progression. EDEM3 predominantly activates the recruit M2‐like macrophages via a glucose metabolism‐dependent mechanism. Blocking glucose utilization antagonizes recruiting and polarizing M2‐like macrophages synergistically with PD‐1 antibody to improve anticancer immunity. |
| format | Article |
| id | doaj-art-eb5c571e1c8c4a04b38a5ff93362f5e7 |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-eb5c571e1c8c4a04b38a5ff93362f5e72025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70161Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockadeShaoyong Peng0Minshan Wu1Qian Yan2Gaopo Xu3Yumo Xie4Guannan Tang5Jinxin Lin6Zixu Yuan7Xiaoxia Liang8Ze Yuan9Jingrong Weng10Liangliang Bai11Xiaolin Wang12Huichuan Yu13Meijin Huang14Yanxin Luo15Xiaoxia Liu16Department of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaGuangdong Institute of Gastroenterology Guangzhou Guangdong ChinaGuangdong Institute of Gastroenterology Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaGuangdong Institute of Gastroenterology Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaGuangdong Institute of Gastroenterology Guangzhou Guangdong ChinaGuangdong Institute of Gastroenterology Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaSchool of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou Guangdong ChinaGuangdong Institute of Gastroenterology Guangzhou Guangdong ChinaGuangdong Institute of Gastroenterology Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong ChinaAbstract Background Immunotherapy is beneficial for some colorectal cancer (CRC) patients, but immunosuppressive networks limit its effectiveness. Cancer‐associatedfibroblasts (CAFs) are significant in immune escape and resistance toimmunotherapy, emphasizing the urgent need for new treatment strategies. Methods Flow cytometric, Western blotting, proteomics analysis, analysis of public database data, genetically modified cell line models, T cell coculture, crystal violetstaining, ELISA, metabonomic and clinical tumour samples were conducted to assess the role of EDEM3 in immune escape and itsmolecular mechanisms. We evaluated theeffects of FMD plus 2‐DG on antitumour immunity using multipleximmunofluorescence, flow cytometry, cytokine profiling, TUNEL assays, xenografttumours, and in vivo studies. Results We show thatCAFs upregulate PD‐L1 glycosylation and contribute to immune evasion byglycosyltransferase EDEM3. Additionally, EDEM3 plays a role in tumour immunityduring tumour progression. However, the EDEM3‐mediated upregulation of PD‐L1 expression underpins PD‐1/PD‐L1 blockade resistance in vivo. This finding contradictsthe previous trend that positive PD‐L1 expression indicates a strong responseto PD‐1/PD‐L1 blockade. Mechanistically, high‐EDEM3 expression facilitates M2‐like This finding contradictsthe previous trend that positive PD‐L1 expression indicates a strong responseto PD‐1/PD‐L1 blockade.Mechanistically, polarizationand chemotactic migration of macrophages, which are enriched in theperipheral region of tumours compared to thecore region, precluding access of CD8+ T cells to tumourfoci. Furthermore, we EDEM3 predominantly activates the recruited M2‐like macrophagesvia a glucose metabolism‐dependent mechanism. Manipulationof glucose utilization by a fasting‐mimicking diet(FMD) plus 2‐DG treatmentsynergistically with PD‐1 antibody elicits potent antitumour activity byeffectively decreasing tumour glycosylated PD‐L1 expression, augmenting the CD8+effector T cell infiltration and activation while concurrently reducing the infiltration.TheCAFs‐EDEM3‐M2‐like macrophage axis plays a critical role in promotingimmunotherapy resistance. infiltration.TheCAFs‐EDEM3‐M2‐like macrophage axis plays a critical role in promotingimmunotherapy resistance. Conclusions Our study suggests that blocking EDEM3‐induced M2‐like macro phage trafficking by FMD plus 2‐DG is a promising and effective strategy to overcomeresistance to checkpoint blockade therapy offeringhope for improved treatment outcomes. Key points Cancer‐associated fibroblasts (CAFs) can enhance PD‐L1 glycosylation through the glycosyltransferase EDEM3, contributing to immune evasion during tumour progression. EDEM3 predominantly activates the recruit M2‐like macrophages via a glucose metabolism‐dependent mechanism. Blocking glucose utilization antagonizes recruiting and polarizing M2‐like macrophages synergistically with PD‐1 antibody to improve anticancer immunity.https://doi.org/10.1002/ctm2.701612‐DGantitumour immunitycancer‐associated fibroblastsfasting‐mimicking dietglycosyltransferase EDEM3M2‐like macrophage |
| spellingShingle | Shaoyong Peng Minshan Wu Qian Yan Gaopo Xu Yumo Xie Guannan Tang Jinxin Lin Zixu Yuan Xiaoxia Liang Ze Yuan Jingrong Weng Liangliang Bai Xiaolin Wang Huichuan Yu Meijin Huang Yanxin Luo Xiaoxia Liu Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockade Clinical and Translational Medicine 2‐DG antitumour immunity cancer‐associated fibroblasts fasting‐mimicking diet glycosyltransferase EDEM3 M2‐like macrophage |
| title | Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockade |
| title_full | Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockade |
| title_fullStr | Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockade |
| title_full_unstemmed | Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockade |
| title_short | Disrupting EDEM3‐induced M2‐like macrophage trafficking by glucose restriction overcomes resistance to PD‐1/PD‐L1 blockade |
| title_sort | disrupting edem3 induced m2 like macrophage trafficking by glucose restriction overcomes resistance to pd 1 pd l1 blockade |
| topic | 2‐DG antitumour immunity cancer‐associated fibroblasts fasting‐mimicking diet glycosyltransferase EDEM3 M2‐like macrophage |
| url | https://doi.org/10.1002/ctm2.70161 |
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