Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma
Background While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/7/e008811.full |
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| _version_ | 1850027706469580800 |
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| author | Yu Chen Yang Chen Yu Zhou Yongsheng Li Ran Ren Juan Lei |
| author_facet | Yu Chen Yang Chen Yu Zhou Yongsheng Li Ran Ren Juan Lei |
| author_sort | Yu Chen |
| collection | DOAJ |
| description | Background While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.Methods Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment’s cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments.Results We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells.Conclusions These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches. |
| format | Article |
| id | doaj-art-07c404bd77a74d24a649c8299feecb07 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-07c404bd77a74d24a649c8299feecb072025-08-20T03:00:04ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2024-008811Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinomaYu Chen0Yang Chen1Yu Zhou2Yongsheng Li3Ran Ren4Juan Lei51 School of Art and Communication, Fujian Polytechnic Normal University, Fuzhou, Fujian, ChinaThe Affiliated Hospital of Qingdao University, Qingdao, Shandong, ChinaDepartment of Nursing, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, Chongqing, ChinaDepartment of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, Chongqing, ChinaDepartment of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, Chongqing, ChinaBackground While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.Methods Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment’s cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments.Results We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells.Conclusions These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.https://jitc.bmj.com/content/12/7/e008811.full |
| spellingShingle | Yu Chen Yang Chen Yu Zhou Yongsheng Li Ran Ren Juan Lei Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma Journal for ImmunoTherapy of Cancer |
| title | Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma |
| title_full | Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma |
| title_fullStr | Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma |
| title_full_unstemmed | Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma |
| title_short | Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma |
| title_sort | harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma |
| url | https://jitc.bmj.com/content/12/7/e008811.full |
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