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Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients

BACKGROUND: Human 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...

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Autores principales: Lin, Zhen, Meng, Xianyi, Wen, Jinming, Corral, José María, Andreev, Darja, Kachler, Katerina, Schett, Georg, Chen, Xiaoxiang, Bozec, Aline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747763/
https://www.ncbi.nlm.nih.gov/pubmed/33344244
http://dx.doi.org/10.3389/fonc.2020.596493
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author Lin, Zhen
Meng, Xianyi
Wen, Jinming
Corral, José María
Andreev, Darja
Kachler, Katerina
Schett, Georg
Chen, Xiaoxiang
Bozec, Aline
author_facet Lin, Zhen
Meng, Xianyi
Wen, Jinming
Corral, José María
Andreev, Darja
Kachler, Katerina
Schett, Georg
Chen, Xiaoxiang
Bozec, Aline
author_sort Lin, Zhen
collection PubMed
description BACKGROUND: Human 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). METHODS: Clonal 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. RESULTS: Tumors 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). CONCLUSIONS: Highly 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.
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spelling pubmed-77477632020-12-19 Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients Lin, Zhen Meng, Xianyi Wen, Jinming Corral, José María Andreev, Darja Kachler, Katerina Schett, Georg Chen, Xiaoxiang Bozec, Aline Front Oncol Oncology BACKGROUND: Human 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). METHODS: Clonal 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. RESULTS: Tumors 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). CONCLUSIONS: Highly 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. Frontiers Media S.A. 2020-12-04 /pmc/articles/PMC7747763/ /pubmed/33344244 http://dx.doi.org/10.3389/fonc.2020.596493 Text en Copyright © 2020 Lin, Meng, Wen, Corral, Andreev, Kachler, Schett, Chen and Bozec http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Lin, Zhen
Meng, Xianyi
Wen, Jinming
Corral, José María
Andreev, Darja
Kachler, Katerina
Schett, Georg
Chen, Xiaoxiang
Bozec, Aline
Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients
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 Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747763/
https://www.ncbi.nlm.nih.gov/pubmed/33344244
http://dx.doi.org/10.3389/fonc.2020.596493
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