Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature
BackgroundIntrahepatic cholangiocarcinoma (ICC) typically exhibits poor responsiveness to immune checkpoint inhibitors (ICIs) due to its microsatellite-stable (MSS) status and low tumor mutational burden (TMB). Conventional biomarkers like PD-L1 expression show limited predictive value, creating an...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1616361/full |
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| author | Xiaofang Li Xiaofang Li Liao Wang Liao Wang Shuang Li Shuang Li |
| author_facet | Xiaofang Li Xiaofang Li Liao Wang Liao Wang Shuang Li Shuang Li |
| author_sort | Xiaofang Li |
| collection | DOAJ |
| description | BackgroundIntrahepatic cholangiocarcinoma (ICC) typically exhibits poor responsiveness to immune checkpoint inhibitors (ICIs) due to its microsatellite-stable (MSS) status and low tumor mutational burden (TMB). Conventional biomarkers like PD-L1 expression show limited predictive value, creating an urgent need for novel therapeutic targets in this aggressive malignancy.Case presentationWe describe a stage IV ICC patient with PD-L1 positivity and a somatic KMT2D mutation (p.R5303C) who attained sustained complete remission after pembrolizumab treatment, despite developing severe multi-organ immune-related adverse events (irAEs) including hepatitis, pneumonitis, and thrombocytopenia. Mechanistic analysis revealed that KMT2D deficiency potentially remodeled the tumor immune microenvironment through epigenetic reprogramming, characterized by enhanced CD8+ T-cell infiltration.ConclusionsOur findings advocate for combinatorial biomarker strategies incorporating epigenetic markers (KMT2D status) with PD-L1 expression to optimize ICI patient selection, while highlighting the need for vigilant toxicity monitoring in this subset. |
| format | Article |
| id | doaj-art-9a1805ce9cc34e5db0e50020c916bf2c |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-9a1805ce9cc34e5db0e50020c916bf2c2025-08-20T03:36:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16163611616361Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literatureXiaofang Li0Xiaofang Li1Liao Wang2Liao Wang3Shuang Li4Shuang Li5Shanxi Bethune Hospital Cancer Center, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Digestive System Oncology Department, Taiyuan, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaShanxi Bethune Hospital Cancer Center, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Lymphoma department, Taiyuan, ChinaShanxi Bethune Hospital Cancer Center, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Digestive System Oncology Department, Taiyuan, ChinaTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaBackgroundIntrahepatic cholangiocarcinoma (ICC) typically exhibits poor responsiveness to immune checkpoint inhibitors (ICIs) due to its microsatellite-stable (MSS) status and low tumor mutational burden (TMB). Conventional biomarkers like PD-L1 expression show limited predictive value, creating an urgent need for novel therapeutic targets in this aggressive malignancy.Case presentationWe describe a stage IV ICC patient with PD-L1 positivity and a somatic KMT2D mutation (p.R5303C) who attained sustained complete remission after pembrolizumab treatment, despite developing severe multi-organ immune-related adverse events (irAEs) including hepatitis, pneumonitis, and thrombocytopenia. Mechanistic analysis revealed that KMT2D deficiency potentially remodeled the tumor immune microenvironment through epigenetic reprogramming, characterized by enhanced CD8+ T-cell infiltration.ConclusionsOur findings advocate for combinatorial biomarker strategies incorporating epigenetic markers (KMT2D status) with PD-L1 expression to optimize ICI patient selection, while highlighting the need for vigilant toxicity monitoring in this subset.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1616361/fullKMT2D mutationsintrahepatic cholangiocarcinomaimmune checkpoint therapypredictive biomarkerspathologic complete response |
| spellingShingle | Xiaofang Li Xiaofang Li Liao Wang Liao Wang Shuang Li Shuang Li Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature Frontiers in Immunology KMT2D mutations intrahepatic cholangiocarcinoma immune checkpoint therapy predictive biomarkers pathologic complete response |
| title | Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature |
| title_full | Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature |
| title_fullStr | Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature |
| title_full_unstemmed | Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature |
| title_short | Lysine methyltransferase 2D deficiency drives complete response to pembrolizumab in PD-L1-High cholangiocarcinoma: a case report and review of literature |
| title_sort | lysine methyltransferase 2d deficiency drives complete response to pembrolizumab in pd l1 high cholangiocarcinoma a case report and review of literature |
| topic | KMT2D mutations intrahepatic cholangiocarcinoma immune checkpoint therapy predictive biomarkers pathologic complete response |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1616361/full |
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