Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma
Background Hepatocellular carcinoma (HCC) is a highly lethal cancer and the second leading cause of cancer-related deaths worldwide. As demonstrated in other solid neoplasms and HCC, infiltrating CD8+ T cells seem to be related to a better prognosis, but the mechanisms affecting the immune landscape...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004031.full |
| _version_ | 1827893844275888128 |
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| author | Akihiko Kawahara Jun Akiba Hirohisa Yano Ambrogio Fassina Rocco Cappellesso Yoshiki Naito Maria Guido Paolo Simioni Giuliana Cortese Lorenzo Nicolè Tiziana Sanavia Valeria Maffeis Claudia Maria Radu Davide Serafin Giacomo Zanus |
| author_facet | Akihiko Kawahara Jun Akiba Hirohisa Yano Ambrogio Fassina Rocco Cappellesso Yoshiki Naito Maria Guido Paolo Simioni Giuliana Cortese Lorenzo Nicolè Tiziana Sanavia Valeria Maffeis Claudia Maria Radu Davide Serafin Giacomo Zanus |
| author_sort | Akihiko Kawahara |
| collection | DOAJ |
| description | Background Hepatocellular carcinoma (HCC) is a highly lethal cancer and the second leading cause of cancer-related deaths worldwide. As demonstrated in other solid neoplasms and HCC, infiltrating CD8+ T cells seem to be related to a better prognosis, but the mechanisms affecting the immune landscape in HCC are still mostly unknown. Necroptosis is a programmed, caspase-independent cell death that, unlike apoptosis, evokes immune response by releasing damage-associated molecular factors. However, in HCC, the relationship between the necroptotic machinery and the tumor-infiltrating lymphocytes has not been fully investigated so far.Methods We investigated the association between the main necroptosis-related genes, that is, RIPK1, RIPK3, MLKL-p, and CD3+/CD8+ tumor-infiltrating T cell by RNA-seq data analysis in 371 patients with primary HCC from The Cancer Genome Atlas and then by immunohistochemistry in two independent cohorts of HCC patients from Italy (82) and Japan (86).Results Our findings highlighted the immunogenetic role of necroptosis and its potential prognostic role in HCC: RIPK1, RIPK3 and MLKL-p were found significantly associated with intratumoral CD3+ and CD8+ T cells. In addition, multivariate survival analysis showed that the expression of RIPK1, RIPK3 and MLKL-p was associated with better overall survival in the two independent cohorts.Conclusions Our results confirmed the immunogenetic properties of necroptosis (NCP) in human HCC, showing that tumor-infiltrating lymphocytes (TILs) and, specifically, CD8+ T cells accumulate in tumors with higher expression of the necroptosis-related genes. These results suggest the importance of further studies to better assess the specific composition, as well as the functional features of the immune environment associated with a necroptotic signature in order to explore new possible diagnostic and immunotherapeutic scenarios. |
| first_indexed | 2024-03-12T21:57:40Z |
| format | Article |
| id | doaj.art-0a285e23f19c4f498713d63cb388c4d4 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:57:40Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-0a285e23f19c4f498713d63cb388c4d42023-07-25T12:35:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004031Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinomaAkihiko Kawahara0Jun Akiba1Hirohisa Yano2Ambrogio Fassina3Rocco Cappellesso4Yoshiki Naito5Maria Guido6Paolo Simioni7Giuliana Cortese8Lorenzo Nicolè9Tiziana Sanavia10Valeria Maffeis11Claudia Maria Radu12Davide Serafin13Giacomo Zanus146 Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan6 Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan11 Department of Pathology, Kurume University School of Medicine, Kurume, Japan1 Department of Medicine (DIMED), University of Padova, Padova, Italy4 Department of Pathology, Padova University Hospital, Padova, Italy6 Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan5 Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy7 Department of Medicine, General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, University of Padova, Padova, Italy8 Department of Statistical Sciences, University of Padova, Padova, Italy1 Department of Medicine (DIMED), University of Padova, Padova, Italy3 Department of Medical Sciences, University of Torino, Torino, Italy5 Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy7 Department of Medicine, General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, University of Padova, Padova, Italy8 Department of Statistical Sciences, University of Padova, Padova, Italy9 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, ItalyBackground Hepatocellular carcinoma (HCC) is a highly lethal cancer and the second leading cause of cancer-related deaths worldwide. As demonstrated in other solid neoplasms and HCC, infiltrating CD8+ T cells seem to be related to a better prognosis, but the mechanisms affecting the immune landscape in HCC are still mostly unknown. Necroptosis is a programmed, caspase-independent cell death that, unlike apoptosis, evokes immune response by releasing damage-associated molecular factors. However, in HCC, the relationship between the necroptotic machinery and the tumor-infiltrating lymphocytes has not been fully investigated so far.Methods We investigated the association between the main necroptosis-related genes, that is, RIPK1, RIPK3, MLKL-p, and CD3+/CD8+ tumor-infiltrating T cell by RNA-seq data analysis in 371 patients with primary HCC from The Cancer Genome Atlas and then by immunohistochemistry in two independent cohorts of HCC patients from Italy (82) and Japan (86).Results Our findings highlighted the immunogenetic role of necroptosis and its potential prognostic role in HCC: RIPK1, RIPK3 and MLKL-p were found significantly associated with intratumoral CD3+ and CD8+ T cells. In addition, multivariate survival analysis showed that the expression of RIPK1, RIPK3 and MLKL-p was associated with better overall survival in the two independent cohorts.Conclusions Our results confirmed the immunogenetic properties of necroptosis (NCP) in human HCC, showing that tumor-infiltrating lymphocytes (TILs) and, specifically, CD8+ T cells accumulate in tumors with higher expression of the necroptosis-related genes. These results suggest the importance of further studies to better assess the specific composition, as well as the functional features of the immune environment associated with a necroptotic signature in order to explore new possible diagnostic and immunotherapeutic scenarios.https://jitc.bmj.com/content/10/3/e004031.full |
| spellingShingle | Akihiko Kawahara Jun Akiba Hirohisa Yano Ambrogio Fassina Rocco Cappellesso Yoshiki Naito Maria Guido Paolo Simioni Giuliana Cortese Lorenzo Nicolè Tiziana Sanavia Valeria Maffeis Claudia Maria Radu Davide Serafin Giacomo Zanus Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma |
| title_full | Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma |
| title_fullStr | Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma |
| title_full_unstemmed | Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma |
| title_short | Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma |
| title_sort | necroptosis driving genes ripk1 ripk3 and mlkl p are associated with intratumoral cd3 and cd8 t cell density and predict prognosis in hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/10/3/e004031.full |
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