<i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype
Considerable advances have been made in lung cancer therapies, but there is still an unmet clinical need to improve survival for lung cancer patients. Immunotherapies have improved survival, although only 20–30% of patients respond to these treatments. Interestingly, cancers with mutations in Kelch-...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/6/3510 |
| _version_ | 1797240689103208448 |
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| author | Christopher J. Occhiuto Karen T. Liby |
| author_facet | Christopher J. Occhiuto Karen T. Liby |
| author_sort | Christopher J. Occhiuto |
| collection | DOAJ |
| description | Considerable advances have been made in lung cancer therapies, but there is still an unmet clinical need to improve survival for lung cancer patients. Immunotherapies have improved survival, although only 20–30% of patients respond to these treatments. Interestingly, cancers with mutations in Kelch-like ECH-associated protein 1 (<i>KEAP1</i>), the negative regulator of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, are resistant to immune checkpoint inhibition and correlate with decreased lymphoid cell infiltration. NRF2 is known for promoting an anti-inflammatory phenotype when activated in immune cells, but the study of NRF2 activation in cancer cells has not been adequately assessed. The objective of this study was to determine how lung cancer cells with constitutive NRF2 activity interact with the immune microenvironment to promote cancer progression. To assess, we generated CRISPR-edited mouse lung cancer cell lines by knocking out the <i>KEAP1</i> or <i>NFE2L2</i> genes and utilized a publicly available single-cell dataset through the Gene Expression Omnibus to investigate tumor/immune cell interactions. We show here that <i>KEAP1</i>-mutant cancers promote immunosuppression of the tumor microenvironment. Our data suggest <i>KEAP1</i> deletion is sufficient to alter the secretion of cytokines, increase expression of immune checkpoint markers on cancer cells, and alter recruitment and differential polarization of immunosuppressive macrophages that ultimately lead to T-cell suppression. |
| first_indexed | 2024-04-24T18:11:25Z |
| format | Article |
| id | doaj.art-78f7826935184b54940a72bbf9aa6993 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:25Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-78f7826935184b54940a72bbf9aa69932024-03-27T13:46:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256351010.3390/ijms25063510<i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage PhenotypeChristopher J. Occhiuto0Karen T. Liby1Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USADepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USAConsiderable advances have been made in lung cancer therapies, but there is still an unmet clinical need to improve survival for lung cancer patients. Immunotherapies have improved survival, although only 20–30% of patients respond to these treatments. Interestingly, cancers with mutations in Kelch-like ECH-associated protein 1 (<i>KEAP1</i>), the negative regulator of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, are resistant to immune checkpoint inhibition and correlate with decreased lymphoid cell infiltration. NRF2 is known for promoting an anti-inflammatory phenotype when activated in immune cells, but the study of NRF2 activation in cancer cells has not been adequately assessed. The objective of this study was to determine how lung cancer cells with constitutive NRF2 activity interact with the immune microenvironment to promote cancer progression. To assess, we generated CRISPR-edited mouse lung cancer cell lines by knocking out the <i>KEAP1</i> or <i>NFE2L2</i> genes and utilized a publicly available single-cell dataset through the Gene Expression Omnibus to investigate tumor/immune cell interactions. We show here that <i>KEAP1</i>-mutant cancers promote immunosuppression of the tumor microenvironment. Our data suggest <i>KEAP1</i> deletion is sufficient to alter the secretion of cytokines, increase expression of immune checkpoint markers on cancer cells, and alter recruitment and differential polarization of immunosuppressive macrophages that ultimately lead to T-cell suppression.https://www.mdpi.com/1422-0067/25/6/3510NRF2 pathwayKEAP1lung cancerimmunosuppressionmacrophagesM2 polarization |
| spellingShingle | Christopher J. Occhiuto Karen T. Liby <i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype International Journal of Molecular Sciences NRF2 pathway KEAP1 lung cancer immunosuppression macrophages M2 polarization |
| title | <i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype |
| title_full | <i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype |
| title_fullStr | <i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype |
| title_full_unstemmed | <i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype |
| title_short | <i>KEAP1</i>-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype |
| title_sort | i keap1 i mutant lung cancers weaken anti tumor immunity and promote an m2 like macrophage phenotype |
| topic | NRF2 pathway KEAP1 lung cancer immunosuppression macrophages M2 polarization |
| url | https://www.mdpi.com/1422-0067/25/6/3510 |
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