Brooksbank Kirsten, Smith Charlotte, Maniati Eleni, Gibson Amy, Tse Wai Yiu, Hall Amy Kate, Wang Jun, Sharp Tyson V, Martin Sarah A
Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Centre for Genomics & Computational Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Neoplasia. 2025 Sep;67:101207. doi: 10.1016/j.neo.2025.101207. Epub 2025 Jul 11.
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.
免疫检查点抑制剂（ICI）在错配修复缺陷（MMRd）癌症的一个亚组中极其有效，但约50%的患者仍对治疗耐药。我们首次表明，这可能是由于不同MMR基因缺失后与ICI反应相关的因子的差异调节所致。在此，我们表明，MMR基因MLH1、MSH2和PMS2缺失后会观察到PD-L1表达增加。然而，MSH6缺失后并非如此，我们表明这是由于MSH6作为PD-L1转录的直接调节因子的新作用，这依赖于组蛋白三甲基转移酶SETD2的招募。MLH1和MSH6基因敲除（KO）细胞的下一代测序显示，与MLH1 KO细胞相比，MSH6 KO细胞的微卫星不稳定性显著更低，尽管MSH6 KO细胞的突变负担更高。这些发现强调了在MMRd队列中进行基因特异性分层的必要性。
Hered Cancer Clin Pract. 2023-10-11
Signal Transduct Target Ther. 2023-8-28
N Engl J Med. 2022-6-23
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