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Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma.

ABSTRACT: The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and copy number alterations. Three subgroups, with "low", "intermediate", and "high" immune signals, were identified in primary tumors and replicated in metastatic tumors. Genes in the low subgroup were enriched for cell-cycle and metabolic pathways, whereas genes in the high subgroup were enriched for IFN and NF-?B signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFN? and NF-?B pathway genes as the regulators of immune suppression. Furthermore, we showed that cigarette smoking, a globally detrimental environmental factor, modulates immunity, reducing the survival primarily in patients with a strong immune response. Together, these analyses identify a set of factors that can be easily assessed that may serve as predictors of response to immunotherapy in patients with melanoma. SIGNIFICANCE: These findings identify novel genetic and environmental modulators of the immune response against primary cutaneous melanoma and predict their impact on patient survival.See related commentary by Anichini, p. 2457.

SUBMITTER: Pozniak J

PROVIDER: S-EPMC6544535 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma.

Poźniak Joanna J Nsengimana Jérémie J Laye Jonathan P JP O'Shea Sally J SJ Diaz Joey Mark S JMS Droop Alastair P AP Filia Anastasia A Harland Mark M Davies John R JR Mell Tracey T Randerson-Moor Juliette A JA Muralidhar Sathya S Hogan Sabrina A SA Freiberger Sandra Nicole SN Levesque Mitchell P MP Cook Graham P GP Bishop D Timothy DT Newton-Bishop Julia J

Cancer research 20190217 10

The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and c ...[more]

PMID: 30773503

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Project description:UNLABELLED:Differences in immunological response among vaccine recipients are determined both by their genetic differences and environmental factors. Knowledge of genetic determinants of immunological response to a vaccine can be used to design a vaccine that circumvents immunogenetic restrictions. The currently available vaccine for typhoid is a pure polysaccharide vaccine, immune response to which is T-cell independent. Little is known about whether genetic variation among vaccinees associates with variation in their antibody response to a polysaccharide vaccine. We conducted a study on 1,000 individuals resident in an area at high-risk for typhoid; vaccinated them with the typhoid vaccine, measured their antibody response to the vaccine, assayed >2,000 curated SNPs chosen from 283 genes that are known to participate in immune-response; and analyzed these data using a strategy to (a) minimize the statistical problems associated with testing of multiple hypotheses, and (b) internally cross-validate inferences, using a half-sample design, with little loss of statistical power. The first stage analysis, using the first half-sample, identified 54 SNPs in 43 genes to be significantly associated with immune response. In the second-stage, these inferences were cross-validated using the second half-sample. First-stage results of only 8 SNPs (out of 54) in 7 genes (out of 43) were cross-validated. We tested additional SNPs in these 7 genes, and found 8 more SNPs to be significantly associated. Haplotypes constructed with these SNPs in these 7 genes also showed significant association. These 7 genes are DEFB1, TLR1, IL1RL1, CTLA4, MAPK8, CD86 and IL17D. The overall picture that has emerged from this study is that (a) immune response to polysaccharide antigens is qualitatively different from that to protein antigens, and (b) polymorphisms in genes involved in polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signaling and eventual production of antimicrobial peptides are associated with antibody response to the polysaccharide vaccine for typhoid. ELECTRONIC SUPPLEMENTARY MATERIAL:The online version of this article (doi:10.1007/s11568-010-9134-1) contains supplementary material, which is available to authorized users.

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Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma.

Publications

Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma.

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