Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma.

Détails

ID Serval
serval:BIB_630A38C698EC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma.
Périodique
Nature cancer
Auteur⸱e⸱s
Haas L., Elewaut A., Gerard C.L., Umkehrer C., Leiendecker L., Pedersen M., Krecioch I., Hoffmann D., Novatchkova M., Kuttke M., Neumann T., da Silva I.P., Witthock H., Cuendet M.A., Carotta S., Harrington K.J., Zuber J., Scolyer R.A., Long G.V., Wilmott J.S., Michielin O., Vanharanta S., Wiesner T., Obenauf A.C.
ISSN
2662-1347 (Electronic)
ISSN-L
2662-1347
Statut éditorial
Publié
Date de publication
07/2021
Peer-reviewed
Oui
Volume
2
Numéro
7
Pages
693-708
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
How targeted therapies and immunotherapies shape tumors, and thereby influence subsequent therapeutic responses, is poorly understood. In the present study, we show, in melanoma patients and mouse models, that when tumors relapse after targeted therapy with MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite the different modes of action of these therapies. We find that cross-resistance is mediated by a cancer cell-instructed, immunosuppressive tumor microenvironment that lacks functional CD103 <sup>+</sup> dendritic cells, precluding an effective T cell response. Restoring the numbers and functionality of CD103 <sup>+</sup> dendritic cells can re-sensitize cross-resistant tumors to immunotherapy. Cross-resistance does not arise from selective pressure of an immune response during evolution of resistance, but from the MAPK pathway, which not only is reactivated, but also exhibits an increased transcriptional output that drives immune evasion. Our work provides mechanistic evidence for cross-resistance between two unrelated therapies, and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy.
Mots-clé
Cancer Research, Oncology
Pubmed
Web of science
Création de la notice
30/07/2021 15:50
Dernière modification de la notice
27/04/2022 5:37
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