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Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

Howell, Rowan; Davies, James; Clarke, Matthew A; Appios, Anna; Mesquita, Inês; Jayal, Yashoda; Ringham-Terry, Ben; ... Bennett, Clare L; + view all (2023) Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling. Science Advances , 9 (15) , Article eadd1992. 10.1126/sciadv.add1992. Green open access

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Abstract

While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC.

Type: Article
Title: Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/sciadv.add1992
Publisher version: https://doi.org/10.1126/sciadv.add1992
Language: English
Additional information: Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/), which permits which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10165767
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