POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma
Objective Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis.D...
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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/e008721.full |
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| author | Yuan Liang Rui Zhang Zheng Liu Hao Wang Haitao Zhao Lei Qiao Mu Liu Ling Lu Jiashuo Chao Mingming Wang Zhengfeng Xuan |
| author_facet | Yuan Liang Rui Zhang Zheng Liu Hao Wang Haitao Zhao Lei Qiao Mu Liu Ling Lu Jiashuo Chao Mingming Wang Zhengfeng Xuan |
| author_sort | Yuan Liang |
| collection | DOAJ |
| description | Objective Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis.Design In this study, to systematically investigate the characteristics of cancer-associated fibroblast (CAF) subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by CAF subsets, we generated an HCC atlas by compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify the specific CAF subsets in the TME that determine the efficacy of immunotherapy in HCC patients.Results Our findings highlight the pivotal role of POSTN+ CAFs as potent immune response barriers at specific tumor locations, as they hinder effective T-cell infiltration and decrease the efficacy of immunotherapy. Additionally, we elucidated the interplay between POSTN+ CAFs and SPP1+ macrophages, whereby the former recruits the latter and triggers increased SPP1 expression via the IL-6/STAT3 signaling pathway. Moreover, we demonstrated a spatial correlation between POSTN+ CAFs and SPP1+ macrophages, revealing an immunosuppressive microenvironment that limits the immunotherapy response. Notably, we found that patients with elevated expression levels of both POSTN+ CAFs and SPP1+ macrophages achieved less therapeutic benefit in an immunotherapy cohort.Conclusion Our research elucidates light on the role of a particular subset of CAFs in immunotherapy resistance, emphasizing the potential benefits of targeting specific CAF subpopulations to improve clinical responses to immunotherapy. |
| format | Article |
| id | doaj-art-51e46dbb62b642a98bbeae3238fdb00c |
| 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-51e46dbb62b642a98bbeae3238fdb00c2025-08-20T03:16:25ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2023-008721POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinomaYuan Liang0Rui Zhang1Zheng Liu2Hao Wang3Haitao Zhao4Lei Qiao5Mu Liu6Ling Lu7Jiashuo Chao8Mingming Wang9Zhengfeng Xuan10Department of Social Medicine and Health Management, Public Health School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China5 Faculty of Social Sciences, University of Macau, Macao SAR, ChinaDepartment of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China1 Department of Critical Care Medicine, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China1 Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, ChinaDepartment of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, ChinaDepartment of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, ChinaObjective Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis.Design In this study, to systematically investigate the characteristics of cancer-associated fibroblast (CAF) subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by CAF subsets, we generated an HCC atlas by compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify the specific CAF subsets in the TME that determine the efficacy of immunotherapy in HCC patients.Results Our findings highlight the pivotal role of POSTN+ CAFs as potent immune response barriers at specific tumor locations, as they hinder effective T-cell infiltration and decrease the efficacy of immunotherapy. Additionally, we elucidated the interplay between POSTN+ CAFs and SPP1+ macrophages, whereby the former recruits the latter and triggers increased SPP1 expression via the IL-6/STAT3 signaling pathway. Moreover, we demonstrated a spatial correlation between POSTN+ CAFs and SPP1+ macrophages, revealing an immunosuppressive microenvironment that limits the immunotherapy response. Notably, we found that patients with elevated expression levels of both POSTN+ CAFs and SPP1+ macrophages achieved less therapeutic benefit in an immunotherapy cohort.Conclusion Our research elucidates light on the role of a particular subset of CAFs in immunotherapy resistance, emphasizing the potential benefits of targeting specific CAF subpopulations to improve clinical responses to immunotherapy.https://jitc.bmj.com/content/12/7/e008721.full |
| spellingShingle | Yuan Liang Rui Zhang Zheng Liu Hao Wang Haitao Zhao Lei Qiao Mu Liu Ling Lu Jiashuo Chao Mingming Wang Zhengfeng Xuan POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma |
| title_full | POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma |
| title_fullStr | POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma |
| title_full_unstemmed | POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma |
| title_short | POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma |
| title_sort | postn cancer associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/12/7/e008721.full |
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