Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients
BackgroundHuman malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a...
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Frontiers Media S.A.
2020-12-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2020.596493/full |
| _version_ | 1818854761295773696 |
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| author | Zhen Lin Zhen Lin Xianyi Meng Xianyi Meng Jinming Wen Jinming Wen José María Corral Darja Andreev Darja Andreev Katerina Kachler Katerina Kachler Georg Schett Georg Schett Xiaoxiang Chen Aline Bozec Aline Bozec |
| author_facet | Zhen Lin Zhen Lin Xianyi Meng Xianyi Meng Jinming Wen Jinming Wen José María Corral Darja Andreev Darja Andreev Katerina Kachler Katerina Kachler Georg Schett Georg Schett Xiaoxiang Chen Aline Bozec Aline Bozec |
| author_sort | Zhen Lin |
| collection | DOAJ |
| description | BackgroundHuman malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA).MethodsClonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan–Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level.ResultsTumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E−07) and cytotoxic pathway score (p = 2.9E−08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e−5) and spleen tyrosine kinase (SYK) (p = 0.0011).ConclusionsHighly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response. |
| first_indexed | 2024-12-19T07:57:51Z |
| format | Article |
| id | doaj.art-6f9ffd91faac4b5fab99af39e5804a8f |
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| language | English |
| last_indexed | 2024-12-19T07:57:51Z |
| publishDate | 2020-12-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-6f9ffd91faac4b5fab99af39e5804a8f2022-12-21T20:29:57ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-12-011010.3389/fonc.2020.596493596493Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma PatientsZhen Lin0Zhen Lin1Xianyi Meng2Xianyi Meng3Jinming Wen4Jinming Wen5José María Corral6Darja Andreev7Darja Andreev8Katerina Kachler9Katerina Kachler10Georg Schett11Georg Schett12Xiaoxiang Chen13Aline Bozec14Aline Bozec15Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDeutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDepartment of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDeutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDepartment of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDeutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDivision of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyDepartment of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDeutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDepartment of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDeutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDepartment of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDeutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDepartment of Rheumatology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyDeutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, GermanyBackgroundHuman malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA).MethodsClonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan–Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level.ResultsTumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E−07) and cytotoxic pathway score (p = 2.9E−08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e−5) and spleen tyrosine kinase (SYK) (p = 0.0011).ConclusionsHighly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response.https://www.frontiersin.org/articles/10.3389/fonc.2020.596493/fullimmunomodulatorintratumor heterogeneityThe Cancer Genome Atlastumor infiltrating lymphocytesmelanoma |
| spellingShingle | Zhen Lin Zhen Lin Xianyi Meng Xianyi Meng Jinming Wen Jinming Wen José María Corral Darja Andreev Darja Andreev Katerina Kachler Katerina Kachler Georg Schett Georg Schett Xiaoxiang Chen Aline Bozec Aline Bozec Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients Frontiers in Oncology immunomodulator intratumor heterogeneity The Cancer Genome Atlas tumor infiltrating lymphocytes melanoma |
| title | Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients |
| title_full | Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients |
| title_fullStr | Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients |
| title_full_unstemmed | Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients |
| title_short | Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients |
| title_sort | intratumor heterogeneity correlates with reduced immune activity and worse survival in melanoma patients |
| topic | immunomodulator intratumor heterogeneity The Cancer Genome Atlas tumor infiltrating lymphocytes melanoma |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2020.596493/full |
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