Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden
Skin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients re...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1006665/full |
| _version_ | 1828306767948283904 |
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| author | George Georgoulias Apostolos Zaravinos Apostolos Zaravinos |
| author_facet | George Georgoulias Apostolos Zaravinos Apostolos Zaravinos |
| author_sort | George Georgoulias |
| collection | DOAJ |
| description | Skin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients respond to therapy. Here, we assessed differential gene expression in primary and metastatic tumors from the TCGA-SKCM dataset, compared to normal skin samples from the GTEx project and validated key findings across 4 independent GEO datasets, as well as using immunohistochemistry in independent patient cohorts. We focused our attention on examining the expression of various immune receptors, immune-cell fractions, immune-related signatures and mutational signatures across cutaneous melanomas with diverse tumor mutation burdens (TMB). Globally, the expression of most immunoreceptors correlated with patient survival, but did not differ between TMBhigh and TMBlow tumors. Melanomas were enriched in “naive T-cell”, “effector memory T-cell”, “exhausted T-cell”, “resting Treg T-cell” and “Th1-like” signatures, irrespective of their BRAF, NF1 or RAS mutational status. Somatic mutations in IDO1 and HLA-DRA were frequent and could be involved in hindering patient response to ICI therapies. We finally analyzed transcriptome profiles of ICI-treated patients and associated their response with high levels of IFNγ, Merck18, CD274, CD8, and low levels of myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and M2 macrophages, irrespective of their TMB status. Overall, our findings highlight the importance of pre-existing T-cell immunity in ICI therapeutic outcomes in skin melanoma and suggest that TMBlow patients could also benefit from such therapies. |
| first_indexed | 2024-04-13T14:48:26Z |
| format | Article |
| id | doaj.art-f93bf33f4b9c4fe8a41d860ef0b935a5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T14:48:26Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f93bf33f4b9c4fe8a41d860ef0b935a52022-12-22T02:42:41ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.10066651006665Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burdenGeorge Georgoulias0Apostolos Zaravinos1Apostolos Zaravinos2Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, CyprusDepartment of Life Sciences, School of Sciences, European University Cyprus, Nicosia, CyprusCancer Genetics, Genomics and Systems Biology laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, CyprusSkin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients respond to therapy. Here, we assessed differential gene expression in primary and metastatic tumors from the TCGA-SKCM dataset, compared to normal skin samples from the GTEx project and validated key findings across 4 independent GEO datasets, as well as using immunohistochemistry in independent patient cohorts. We focused our attention on examining the expression of various immune receptors, immune-cell fractions, immune-related signatures and mutational signatures across cutaneous melanomas with diverse tumor mutation burdens (TMB). Globally, the expression of most immunoreceptors correlated with patient survival, but did not differ between TMBhigh and TMBlow tumors. Melanomas were enriched in “naive T-cell”, “effector memory T-cell”, “exhausted T-cell”, “resting Treg T-cell” and “Th1-like” signatures, irrespective of their BRAF, NF1 or RAS mutational status. Somatic mutations in IDO1 and HLA-DRA were frequent and could be involved in hindering patient response to ICI therapies. We finally analyzed transcriptome profiles of ICI-treated patients and associated their response with high levels of IFNγ, Merck18, CD274, CD8, and low levels of myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and M2 macrophages, irrespective of their TMB status. Overall, our findings highlight the importance of pre-existing T-cell immunity in ICI therapeutic outcomes in skin melanoma and suggest that TMBlow patients could also benefit from such therapies.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1006665/fullskin melanomatumor mutation burden (TMB)immune signaturesimmune checkpoint inhibition therapypatient responsetumor-infiltrating lymphocytes |
| spellingShingle | George Georgoulias Apostolos Zaravinos Apostolos Zaravinos Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden Frontiers in Immunology skin melanoma tumor mutation burden (TMB) immune signatures immune checkpoint inhibition therapy patient response tumor-infiltrating lymphocytes |
| title | Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden |
| title_full | Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden |
| title_fullStr | Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden |
| title_full_unstemmed | Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden |
| title_short | Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden |
| title_sort | genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden |
| topic | skin melanoma tumor mutation burden (TMB) immune signatures immune checkpoint inhibition therapy patient response tumor-infiltrating lymphocytes |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1006665/full |
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