LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade
Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases exp...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2018
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| _version_ | 1826306232628019200 |
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| author | Sheng, W LaFleur, MW Nguyen, TH Chen, S Chakravarthy, A Conway, JR Li, Y Chen, H Yang, H Hsu, P-H Van Allen, EM Freeman, GJ De Carvalho, DD He, HH Sharpe, AH Shi, Y |
| author_facet | Sheng, W LaFleur, MW Nguyen, TH Chen, S Chakravarthy, A Conway, JR Li, Y Chen, H Yang, H Hsu, P-H Van Allen, EM Freeman, GJ De Carvalho, DD He, HH Sharpe, AH Shi, Y |
| author_sort | Sheng, W |
| collection | OXFORD |
| description | Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy. |
| first_indexed | 2024-03-07T06:44:49Z |
| format | Journal article |
| id | oxford-uuid:fa821e87-9023-479f-a935-e08b0d47b200 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:44:49Z |
| publishDate | 2018 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:fa821e87-9023-479f-a935-e08b0d47b2002022-03-27T13:06:34ZLSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockadeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fa821e87-9023-479f-a935-e08b0d47b200EnglishSymplectic ElementsCell Press2018Sheng, WLaFleur, MWNguyen, THChen, SChakravarthy, AConway, JRLi, YChen, HYang, HHsu, P-HVan Allen, EMFreeman, GJDe Carvalho, DDHe, HHSharpe, AHShi, YChromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy. |
| spellingShingle | Sheng, W LaFleur, MW Nguyen, TH Chen, S Chakravarthy, A Conway, JR Li, Y Chen, H Yang, H Hsu, P-H Van Allen, EM Freeman, GJ De Carvalho, DD He, HH Sharpe, AH Shi, Y LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade |
| title | LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade |
| title_full | LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade |
| title_fullStr | LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade |
| title_full_unstemmed | LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade |
| title_short | LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade |
| title_sort | lsd1 ablation stimulates anti tumor immunity and enables checkpoint blockade |
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