Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients
Abstract Background Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant pa...
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-023-01905-9 |
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| author | Andrea Sacconi Paola Muti Claudio Pulito Giulia Urbani Matteo Allegretti Raul Pellini Nikolay Mehterov Uri Ben-David Sabrina Strano Paolo Bossi Giovanni Blandino |
| author_facet | Andrea Sacconi Paola Muti Claudio Pulito Giulia Urbani Matteo Allegretti Raul Pellini Nikolay Mehterov Uri Ben-David Sabrina Strano Paolo Bossi Giovanni Blandino |
| author_sort | Andrea Sacconi |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. Methods We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines. Results We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings. Conclusions Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting. |
| first_indexed | 2024-03-09T05:55:43Z |
| format | Article |
| id | doaj.art-d78903983c76433080b685a34a6e160d |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-09T05:55:43Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-d78903983c76433080b685a34a6e160d2023-12-03T12:14:21ZengBMCMolecular Cancer1476-45982023-11-0122111110.1186/s12943-023-01905-9Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patientsAndrea Sacconi0Paola Muti1Claudio Pulito2Giulia Urbani3Matteo Allegretti4Raul Pellini5Nikolay Mehterov6Uri Ben-David7Sabrina Strano8Paolo Bossi9Giovanni Blandino10Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer InstituteDepartment of Biomedical, Surgical Science and Oral Health, Milan UniversityTranslational Oncology Research Unit, IRCCS Regina Elena National Cancer InstituteTranslational Oncology Research Unit, IRCCS Regina Elena National Cancer InstituteTranslational Oncology Research Unit, IRCCS Regina Elena National Cancer InstituteOtolaryngology Head and Neck Surgery Unit, IRCCS Regina Elena National Cancer InstituteDepartment of Medical Biology, Medical University-PlovdivDepartment of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv UniversitySAFU Unit, IRCCS Regina Elena National Cancer InstituteDepartment of Biomedical Sciences, Humanitas UniversityTranslational Oncology Research Unit, IRCCS Regina Elena National Cancer InstituteAbstract Background Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. Methods We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines. Results We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings. Conclusions Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting.https://doi.org/10.1186/s12943-023-01905-9HNSCCImmunotherapyImmune checkpoint inhibitorp53PDL1c-MYC |
| spellingShingle | Andrea Sacconi Paola Muti Claudio Pulito Giulia Urbani Matteo Allegretti Raul Pellini Nikolay Mehterov Uri Ben-David Sabrina Strano Paolo Bossi Giovanni Blandino Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients Molecular Cancer HNSCC Immunotherapy Immune checkpoint inhibitor p53 PDL1 c-MYC |
| title | Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients |
| title_full | Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients |
| title_fullStr | Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients |
| title_full_unstemmed | Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients |
| title_short | Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients |
| title_sort | immunosignatures associated with tp53 status and co mutations classify prognostically head and neck cancer patients |
| topic | HNSCC Immunotherapy Immune checkpoint inhibitor p53 PDL1 c-MYC |
| url | https://doi.org/10.1186/s12943-023-01905-9 |
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