Integrative Analysis of Multi-omics Data Identified EGFR and PTGS2 as Key Nodes in a Gene Regulatory Network Related to Immune Phenotypes in Head and Neck Cancer
©2020 American Association for Cancer Research..
PURPOSE: Malignant progression exhibits a tightly orchestrated balance between immune effector response and tolerance. However, underlying molecular principles that drive the establishment and maintenance of the tumor immune phenotype remain to be elucidated.
EXPERIMENTAL DESIGN: We trained a novel molecular classifier based on immune cell subsets related to programmed death-ligand 1 (PD-L1) and interferon γ (IFNγ) expression, which revealed distinct subgroups with higher (cluster A) or lower (subcluster B3) cytotoxic immune phenotypes. Integrative analysis of multi-omics data was conducted to identify differences in genetic and epigenetic landscapes as well as their impact on differentially expressed genes (DEG) among immune phenotypes. A prognostic gene signature for immune checkpoint inhibition (ICI) was established by a least absolute shrinkage and selection operator (LASSO)-Cox regression model.
RESULTS: Mutational landscape analyses unraveled a higher frequency of CASP8 somatic mutations in subcluster A1, while subcluster B3 exhibited a characteristic pattern of copy-number alterations affecting chemokine signaling and immune effector response. The integrative multi-omics approach identified EGFR and PTGS2 as key nodes in a gene regulatory network related to the immune phenotype, and several DEGs related to the immune phenotypes were affected by EGFR inhibition in tumor cell lines. Finally, we established a prognostic gene signature by a LASSO-Cox regression model based on DEGs between nonprogressive disease and progressive disease subgroups for ICI.
CONCLUSIONS: Our data highlight a complex interplay between genetic and epigenetic events in the establishment of the tumor immune phenotype and provide compelling experimental evidence that a patient with squamous cell carcinoma of the head and neck at higher risk for ICI treatment failure might benefit from a combination with EGFR inhibition.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 26(2020), 14 vom: 15. Juli, Seite 3616-3628 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Feng, Bohai [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.11.2021 Date Revised 02.11.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-19-3997 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM307493172 |
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| 100 | 1 | |a Feng, Bohai |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Integrative Analysis of Multi-omics Data Identified EGFR and PTGS2 as Key Nodes in a Gene Regulatory Network Related to Immune Phenotypes in Head and Neck Cancer |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 02.11.2021 | ||
| 500 | |a Date Revised 02.11.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2020 American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Malignant progression exhibits a tightly orchestrated balance between immune effector response and tolerance. However, underlying molecular principles that drive the establishment and maintenance of the tumor immune phenotype remain to be elucidated | ||
| 520 | |a EXPERIMENTAL DESIGN: We trained a novel molecular classifier based on immune cell subsets related to programmed death-ligand 1 (PD-L1) and interferon γ (IFNγ) expression, which revealed distinct subgroups with higher (cluster A) or lower (subcluster B3) cytotoxic immune phenotypes. Integrative analysis of multi-omics data was conducted to identify differences in genetic and epigenetic landscapes as well as their impact on differentially expressed genes (DEG) among immune phenotypes. A prognostic gene signature for immune checkpoint inhibition (ICI) was established by a least absolute shrinkage and selection operator (LASSO)-Cox regression model | ||
| 520 | |a RESULTS: Mutational landscape analyses unraveled a higher frequency of CASP8 somatic mutations in subcluster A1, while subcluster B3 exhibited a characteristic pattern of copy-number alterations affecting chemokine signaling and immune effector response. The integrative multi-omics approach identified EGFR and PTGS2 as key nodes in a gene regulatory network related to the immune phenotype, and several DEGs related to the immune phenotypes were affected by EGFR inhibition in tumor cell lines. Finally, we established a prognostic gene signature by a LASSO-Cox regression model based on DEGs between nonprogressive disease and progressive disease subgroups for ICI | ||
| 520 | |a CONCLUSIONS: Our data highlight a complex interplay between genetic and epigenetic events in the establishment of the tumor immune phenotype and provide compelling experimental evidence that a patient with squamous cell carcinoma of the head and neck at higher risk for ICI treatment failure might benefit from a combination with EGFR inhibition | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
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| 700 | 1 | |a Pastor Hostench, Xavier |e verfasserin |4 aut | |
| 700 | 1 | |a Bieg, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Plath, Michaela |e verfasserin |4 aut | |
| 700 | 1 | |a Ishaque, Naveed |e verfasserin |4 aut | |
| 700 | 1 | |a Eils, Roland |e verfasserin |4 aut | |
| 700 | 1 | |a Freier, Kolja |e verfasserin |4 aut | |
| 700 | 1 | |a Weichert, Wilko |e verfasserin |4 aut | |
| 700 | 1 | |a Zaoui, Karim |e verfasserin |4 aut | |
| 700 | 1 | |a Hess, Jochen |e verfasserin |4 aut | |
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