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

Details

Serval ID
serval:BIB_630A38C698EC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma
Journal
Nature Cancer
Author(s)
Haas Lisa, Elewaut Anais, Gerard Camille L., Umkehrer Christian, Leiendecker Lukas, Pedersen Malin, Krecioch Izabela, Hoffmann David, Novatchkova Maria, Kuttke Mario, Neumann Tobias, da Silva Ines Pires, Witthock Harriet, Cuendet Michel A., Carotta Sebastian, Harrington Kevin J., Zuber Johannes, Scolyer Richard A., Long Georgina V., Wilmott James S., Michielin Olivier, Vanharanta Sakari, Wiesner Thomas, Obenauf Anna C.
ISSN
2662-1347
Publication state
Published
Issued date
07/2021
Volume
2
Number
7
Pages
693-708
Language
english
Abstract
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(+) dendritic cells, precluding an effective T cell response. Restoring the numbers and functionality of CD103(+) 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.
Obenauf and colleagues report that acquired resistance to BRAF and MEK inhibitors in melanoma confers cross-resistance to immune checkpoint blockade by fostering a cancer cell-instructed, immune-evasive tumor microenvironment.
Keywords
Cancer Research, Oncology
Web of science
Create date
30/07/2021 15:50
Last modification date
11/12/2021 6:36
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