The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma
Open accessAbstract
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.
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Cites
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Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy
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CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours
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A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma
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Metadata
- Authors
- 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.
- Venue
- Nature Cancer
- Published
- 2021-07-15
- Volume
- 2
- Issue
- 7
- Pages
- 693-708
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W3182981660
- Cited by
- 196
- References
- 17
- FWCI
- 11.33
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma. https://app.cochat.ai/papers/10.1038/s43018-021-00221-9
- The paper
- 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., . . . Obenauf, A. C. (2021). Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma. Nature Cancer. https://doi.org/10.1038/s43018-021-00221-9
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
