The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression
Immune checkpoint inhibitors (ICIs) are extremely effective in a subgroup of mismatch repair-deficient (MMRd) cancers, but ∼50% remain resistant to treatment. We have shown for the first time that this may be due to the differential regulation of factors linked to response to ICIs upon loss of the d...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000879 |
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| _version_ | 1849245829628428288 |
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| author | Kirsten Brooksbank Charlotte Smith Eleni Maniati Amy Gibson Wai Yiu Tse Amy Kate Hall Jun Wang Tyson V Sharp Sarah A Martin |
| author_facet | Kirsten Brooksbank Charlotte Smith Eleni Maniati Amy Gibson Wai Yiu Tse Amy Kate Hall Jun Wang Tyson V Sharp Sarah A Martin |
| author_sort | Kirsten Brooksbank |
| collection | DOAJ |
| description | Immune checkpoint inhibitors (ICIs) are extremely effective in a subgroup of mismatch repair-deficient (MMRd) cancers, but ∼50% remain resistant to treatment. We have shown for the first time that this may be due to the differential regulation of factors linked to response to ICIs upon loss of the different MMR genes. Here, we show that increased PD-L1 expression is observed upon loss of the MMR genes MLH1, MSH2 and PMS2. However, this is not true upon loss of MSH6, and we show that this is due to a novel role for MSH6 as a direct regulator of PD-L1 transcription, dependent on recruitment by the histone trimethyltransferase SETD2. Next-generation sequencing of MLH1 and MSH6 knockout (KO) cells revealed that MSH6 KO cells have significantly lower microsatellite instability in comparison to MLH1 KO cells, despite MSH6 KO cells having a higher mutational burden. These findings emphasise the need for gene-specific stratification in the MMRd cohort. |
| format | Article |
| id | doaj-art-c9edfd0a554142258e66ea86bf099089 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-c9edfd0a554142258e66ea86bf0990892025-08-20T03:58:41ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-09-016710120710.1016/j.neo.2025.101207The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expressionKirsten Brooksbank0Charlotte Smith1Eleni Maniati2Amy Gibson3Wai Yiu Tse4Amy Kate Hall5Jun Wang6Tyson V Sharp7Sarah A Martin8Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Genomics & Computational Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Genomics & Computational Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Corresponding authors.Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Corresponding authors.Immune checkpoint inhibitors (ICIs) are extremely effective in a subgroup of mismatch repair-deficient (MMRd) cancers, but ∼50% remain resistant to treatment. We have shown for the first time that this may be due to the differential regulation of factors linked to response to ICIs upon loss of the different MMR genes. Here, we show that increased PD-L1 expression is observed upon loss of the MMR genes MLH1, MSH2 and PMS2. However, this is not true upon loss of MSH6, and we show that this is due to a novel role for MSH6 as a direct regulator of PD-L1 transcription, dependent on recruitment by the histone trimethyltransferase SETD2. Next-generation sequencing of MLH1 and MSH6 knockout (KO) cells revealed that MSH6 KO cells have significantly lower microsatellite instability in comparison to MLH1 KO cells, despite MSH6 KO cells having a higher mutational burden. These findings emphasise the need for gene-specific stratification in the MMRd cohort.http://www.sciencedirect.com/science/article/pii/S1476558625000879Mismatch repairMSH6Transcription factorPD-L1Immunotherapy |
| spellingShingle | Kirsten Brooksbank Charlotte Smith Eleni Maniati Amy Gibson Wai Yiu Tse Amy Kate Hall Jun Wang Tyson V Sharp Sarah A Martin The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression Neoplasia: An International Journal for Oncology Research Mismatch repair MSH6 Transcription factor PD-L1 Immunotherapy |
| title | The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression |
| title_full | The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression |
| title_fullStr | The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression |
| title_full_unstemmed | The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression |
| title_short | The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression |
| title_sort | dna mismatch repair protein msh6 is a novel regulator of pd l1 expression |
| topic | Mismatch repair MSH6 Transcription factor PD-L1 Immunotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000879 |
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