Toggle Main Menu Toggle Search

Open Access padlockePrints

Genetic and environmental determinants of immune response to cutaneous melanoma

Lookup NU author(s): Dr Jérémie Nsengimana

Downloads


Licence

This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for Cancer Research Inc., 2019.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

© 2019 American Association for Cancer Research.The immune response to melanomaimproves 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-kB signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFNγ and NF-kB 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 thatmay 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 cutaneousmelanoma and predict their impact on patient survival.


Publication metadata

Author(s): Pozniak J, Nsengimana J, Laye JP, O'Shea SJ, Diaz JMS, Droop AlastairP, Filia A, Harland M, Davies JR, Mell T, Randerson-Moor JA, Muralidhar S, Hogan SA, Freiberger SN, Levesque MP, Cook GP, Bishop DT, Newton-Bishop J

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2019

Volume: 79

Issue: 10

Pages: 2684-2696

Online publication date: 01/05/2019

Acceptance date: 25/01/2019

Date deposited: 25/06/2020

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

Publisher: American Association for Cancer Research Inc.

URL: https://doi.org/10.1158/0008-5472.CAN-18-2864

DOI: 10.1158/0008-5472.CAN-18-2864

PubMed id: 30773503


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share