Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade
Abstract Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KE...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-03-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-023-00362-3 |
| _version_ | 1797429464490049536 |
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| author | Douglas B. Fox Richard Y. Ebright Xin Hong Hunter C. Russell Hongshan Guo Thomas J. LaSalle Ben S. Wittner Nicolas Poux Joanna A. Vuille Mehmet Toner Nir Hacohen Genevieve M. Boland Debattama R. Sen Ryan J. Sullivan Shyamala Maheswaran Daniel A. Haber |
| author_facet | Douglas B. Fox Richard Y. Ebright Xin Hong Hunter C. Russell Hongshan Guo Thomas J. LaSalle Ben S. Wittner Nicolas Poux Joanna A. Vuille Mehmet Toner Nir Hacohen Genevieve M. Boland Debattama R. Sen Ryan J. Sullivan Shyamala Maheswaran Daniel A. Haber |
| author_sort | Douglas B. Fox |
| collection | DOAJ |
| description | Abstract Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance. |
| first_indexed | 2024-03-09T09:13:32Z |
| format | Article |
| id | doaj.art-0c4c7c44430b4c2d974ab834570483bb |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T09:13:32Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-0c4c7c44430b4c2d974ab834570483bb2023-12-02T07:48:06ZengNature Portfolionpj Precision Oncology2397-768X2023-03-01711710.1038/s41698-023-00362-3Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockadeDouglas B. Fox0Richard Y. Ebright1Xin Hong2Hunter C. Russell3Hongshan Guo4Thomas J. LaSalle5Ben S. Wittner6Nicolas Poux7Joanna A. Vuille8Mehmet Toner9Nir Hacohen10Genevieve M. Boland11Debattama R. Sen12Ryan J. Sullivan13Shyamala Maheswaran14Daniel A. Haber15Massachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolCenter for Engineering in Medicine, Massachusetts General Hospital and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolMassachusetts General Hospital Cancer Center and Harvard Medical SchoolAbstract Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.https://doi.org/10.1038/s41698-023-00362-3 |
| spellingShingle | Douglas B. Fox Richard Y. Ebright Xin Hong Hunter C. Russell Hongshan Guo Thomas J. LaSalle Ben S. Wittner Nicolas Poux Joanna A. Vuille Mehmet Toner Nir Hacohen Genevieve M. Boland Debattama R. Sen Ryan J. Sullivan Shyamala Maheswaran Daniel A. Haber Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade npj Precision Oncology |
| title | Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade |
| title_full | Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade |
| title_fullStr | Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade |
| title_full_unstemmed | Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade |
| title_short | Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade |
| title_sort | downregulation of keap1 in melanoma promotes resistance to immune checkpoint blockade |
| url | https://doi.org/10.1038/s41698-023-00362-3 |
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