Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma
IntroductionThe conflict between cancer cells and the host immune system shapes the immune tumour microenvironment (TME) in hepatocellular carcinoma (HCC). A deep understanding of the heterogeneity and intercellular communication network in the TME of HCC will provide promising strategies to orchest...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1164448/full |
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| author | Ang Li Bai Ji Yongsheng Yang Bicheng Ye Qinmei Zhu Xintong Hu Yong Liu Peiwen Zhou Juanjuan Liu Ranran Gao Qi Zhou Boxi Kang Yanfang Jiang |
| author_facet | Ang Li Bai Ji Yongsheng Yang Bicheng Ye Qinmei Zhu Xintong Hu Yong Liu Peiwen Zhou Juanjuan Liu Ranran Gao Qi Zhou Boxi Kang Yanfang Jiang |
| author_sort | Ang Li |
| collection | DOAJ |
| description | IntroductionThe conflict between cancer cells and the host immune system shapes the immune tumour microenvironment (TME) in hepatocellular carcinoma (HCC). A deep understanding of the heterogeneity and intercellular communication network in the TME of HCC will provide promising strategies to orchestrate the immune system to target and eradicate cancers.MethodsHere, we performed single-cell RNA sequencing (scRNA-seq) and computational analysis of 35786 unselected single cells from 3 human HCC tumour and 3 matched adjacent samples to elucidate the heterogeneity and intercellular communication network of the TME. The specific lysis of HCC cell lines was examined in vitro using cytotoxicity assays. Granzyme B concentration in supernatants of cytotoxicity assays was measured by ELISA.ResultsWe found that VCAN+ tumour-associated macrophages (TAMs) might undergo M2-like polarization and differentiate in the tumour region. Regulatory dendritic cells (DCs) exhibited immune regulatory and tolerogenic phenotypes in the TME. Furthermore, we observed intensive potential intercellular crosstalk among C1QC+ TAMs, regulatory DCs, regulator T (Treg) cells, and exhausted CD8+ T cells that fostered an immunosuppressive niche in the HCC TME. Moreover, we identified that the TIGIT-PVR/PVRL2 axis provides a prominent coinhibitory signal in the immunosuppressive TME. In vitro, antibody blockade of PVR or PVRL2 on HCC cell lines or TIGIT blockade on immune cells increased immune cell-mediated lysis of tumour cell. This enhanced immune response is paralleled by the increased secretion of Granzyme B by immune cells.DiscussionCollectively, our study revealed the functional state, clinical significance, and intercellular communication of immunosuppressive cells in HCC at single-cell resolution. Moreover, PVR/PVRL2, interact with TIGIT act as prominent coinhibitory signals and might represent a promising, efficacious immunotherapy strategy in HCC. |
| first_indexed | 2024-03-13T05:56:38Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T05:56:38Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-1ed91721c6ea4619a53de6b4b3df24342023-06-13T04:28:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.11644481164448Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinomaAng Li0Bai Ji1Yongsheng Yang2Bicheng Ye3Qinmei Zhu4Xintong Hu5Yong Liu6Peiwen Zhou7Juanjuan Liu8Ranran Gao9Qi Zhou10Boxi Kang11Yanfang Jiang12Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, the First Hospital of Jilin University, Changchun, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun, ChinaDepartment of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun, ChinaSchool of Clinical Medicine, Medical College of Yangzhou Polytechnic College, Yangzhou, ChinaSchool of Clinical Medicine, Medical College of Yangzhou Polytechnic College, Yangzhou, ChinaKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, the First Hospital of Jilin University, Changchun, ChinaKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, the First Hospital of Jilin University, Changchun, ChinaKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, the First Hospital of Jilin University, Changchun, ChinaDepartment of Bioinformatics, Analytical Biosciences Limited, Beijing, ChinaDepartment of Bioinformatics, Analytical Biosciences Limited, Beijing, ChinaDepartment of Bioinformatics, Analytical Biosciences Limited, Beijing, ChinaDepartment of Bioinformatics, Analytical Biosciences Limited, Beijing, ChinaKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, the First Hospital of Jilin University, Changchun, ChinaIntroductionThe conflict between cancer cells and the host immune system shapes the immune tumour microenvironment (TME) in hepatocellular carcinoma (HCC). A deep understanding of the heterogeneity and intercellular communication network in the TME of HCC will provide promising strategies to orchestrate the immune system to target and eradicate cancers.MethodsHere, we performed single-cell RNA sequencing (scRNA-seq) and computational analysis of 35786 unselected single cells from 3 human HCC tumour and 3 matched adjacent samples to elucidate the heterogeneity and intercellular communication network of the TME. The specific lysis of HCC cell lines was examined in vitro using cytotoxicity assays. Granzyme B concentration in supernatants of cytotoxicity assays was measured by ELISA.ResultsWe found that VCAN+ tumour-associated macrophages (TAMs) might undergo M2-like polarization and differentiate in the tumour region. Regulatory dendritic cells (DCs) exhibited immune regulatory and tolerogenic phenotypes in the TME. Furthermore, we observed intensive potential intercellular crosstalk among C1QC+ TAMs, regulatory DCs, regulator T (Treg) cells, and exhausted CD8+ T cells that fostered an immunosuppressive niche in the HCC TME. Moreover, we identified that the TIGIT-PVR/PVRL2 axis provides a prominent coinhibitory signal in the immunosuppressive TME. In vitro, antibody blockade of PVR or PVRL2 on HCC cell lines or TIGIT blockade on immune cells increased immune cell-mediated lysis of tumour cell. This enhanced immune response is paralleled by the increased secretion of Granzyme B by immune cells.DiscussionCollectively, our study revealed the functional state, clinical significance, and intercellular communication of immunosuppressive cells in HCC at single-cell resolution. Moreover, PVR/PVRL2, interact with TIGIT act as prominent coinhibitory signals and might represent a promising, efficacious immunotherapy strategy in HCC.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1164448/fullsingle-cell RNA sequencingHCCTMEimmunotherapyPVR/PVRL2 |
| spellingShingle | Ang Li Bai Ji Yongsheng Yang Bicheng Ye Qinmei Zhu Xintong Hu Yong Liu Peiwen Zhou Juanjuan Liu Ranran Gao Qi Zhou Boxi Kang Yanfang Jiang Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma Frontiers in Immunology single-cell RNA sequencing HCC TME immunotherapy PVR/PVRL2 |
| title | Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma |
| title_full | Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma |
| title_fullStr | Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma |
| title_full_unstemmed | Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma |
| title_short | Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma |
| title_sort | single cell rna sequencing highlights the role of pvr pvrl2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma |
| topic | single-cell RNA sequencing HCC TME immunotherapy PVR/PVRL2 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1164448/full |
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