Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer
Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. However, PDAC with germline BRCA mutations, which lead to homologous recombination (HR) deficiency (HRD), demonstrated an increased sensitivity to platinum-based chemotherapy regimens. This increased chemosensitivi...
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BMC
2025-06-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-025-00673-0 |
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| author | Mengyue Lei Jessica Gai Thomas J. McPhaul Huijuan Luo Penghui Lin Dongbing Liu Michael Pishvaian Nicholas J. Roberts Kui Wu Jin He Lei Zheng |
| author_facet | Mengyue Lei Jessica Gai Thomas J. McPhaul Huijuan Luo Penghui Lin Dongbing Liu Michael Pishvaian Nicholas J. Roberts Kui Wu Jin He Lei Zheng |
| author_sort | Mengyue Lei |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. However, PDAC with germline BRCA mutations, which lead to homologous recombination (HR) deficiency (HRD), demonstrated an increased sensitivity to platinum-based chemotherapy regimens. This increased chemosensitivity was also seen in PDACs with germline or somatic mutations in the DNA double-strand damage response (DDR) genes beyond canonical HR genes such as BRCA1, BRCA2, and PALB2. However, there are no consensus methods to determine HRD status; and neither is there a well-defined list of HR-DDR genes. In addition, how HRD and/or HR-DDR gene mutation status impacts the tumor immune microenvironment including tumor mutation burden (TMB), neoantigen load, T cell receptor (TCR) repertoire, and effector T cell infiltration is unknown. Thus, in this study, we developed a new method to categorize PDACs into HRD-positive and HRD-negative subgroups by using results from whole exome sequencing, whole genome sequencing, or both into consideration. We classified a cohort of 89 PDACs into HRD-positive (n = 18) and HRD-negative (n = 69) tumors. HR-DDR gene variants were identified more frequently in HRD-positive PDACs than HRD-negative PDACs, with RAD51B, BRCA2 and ATM alterations most frequently identified in HRD-positive PDACs. Notably, TMB and neoantigen load was significantly higher in HRD-positive PDACs compared to HRD-negative tumors. Interestingly, HRD-positive PDACs, PDACs with high tumor mutational burden, and PDAC with high neoantigen load were all associated with lower CD8 + T lymphocyte infiltration and T cell clonal diversity, suggesting a mechanism of resistance to immune checkpoint inhibitors (ICIs). Therefore, this study suggests that treatments to enhance effector T cell infiltration and T cell clonal diversity may overcome resistance to ICI-based immunotherapy in HRD-positive PDACs. |
| format | Article |
| id | doaj-art-37a6797a6fac4ca8b4b5c8731cf4c028 |
| institution | OA Journals |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Experimental Hematology & Oncology |
| spelling | doaj-art-37a6797a6fac4ca8b4b5c8731cf4c0282025-08-20T02:10:36ZengBMCExperimental Hematology & Oncology2162-36192025-06-011411610.1186/s40164-025-00673-0Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancerMengyue Lei0Jessica Gai1Thomas J. McPhaul2Huijuan Luo3Penghui Lin4Dongbing Liu5Michael Pishvaian6Nicholas J. Roberts7Kui Wu8Jin He9Lei Zheng10Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI ResearchSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineGuangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI ResearchGuangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI ResearchGuangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI ResearchSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineGuangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI ResearchSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineAbstract Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. However, PDAC with germline BRCA mutations, which lead to homologous recombination (HR) deficiency (HRD), demonstrated an increased sensitivity to platinum-based chemotherapy regimens. This increased chemosensitivity was also seen in PDACs with germline or somatic mutations in the DNA double-strand damage response (DDR) genes beyond canonical HR genes such as BRCA1, BRCA2, and PALB2. However, there are no consensus methods to determine HRD status; and neither is there a well-defined list of HR-DDR genes. In addition, how HRD and/or HR-DDR gene mutation status impacts the tumor immune microenvironment including tumor mutation burden (TMB), neoantigen load, T cell receptor (TCR) repertoire, and effector T cell infiltration is unknown. Thus, in this study, we developed a new method to categorize PDACs into HRD-positive and HRD-negative subgroups by using results from whole exome sequencing, whole genome sequencing, or both into consideration. We classified a cohort of 89 PDACs into HRD-positive (n = 18) and HRD-negative (n = 69) tumors. HR-DDR gene variants were identified more frequently in HRD-positive PDACs than HRD-negative PDACs, with RAD51B, BRCA2 and ATM alterations most frequently identified in HRD-positive PDACs. Notably, TMB and neoantigen load was significantly higher in HRD-positive PDACs compared to HRD-negative tumors. Interestingly, HRD-positive PDACs, PDACs with high tumor mutational burden, and PDAC with high neoantigen load were all associated with lower CD8 + T lymphocyte infiltration and T cell clonal diversity, suggesting a mechanism of resistance to immune checkpoint inhibitors (ICIs). Therefore, this study suggests that treatments to enhance effector T cell infiltration and T cell clonal diversity may overcome resistance to ICI-based immunotherapy in HRD-positive PDACs.https://doi.org/10.1186/s40164-025-00673-0Pancreatic ductal adenocarcinoma (PDAC)Homologous recombination-DNA damage response defectsTumor mutation burden (TMB)T cell infiltrationT cell clonal diversityImmune checkpoint inhibitors |
| spellingShingle | Mengyue Lei Jessica Gai Thomas J. McPhaul Huijuan Luo Penghui Lin Dongbing Liu Michael Pishvaian Nicholas J. Roberts Kui Wu Jin He Lei Zheng Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer Experimental Hematology & Oncology Pancreatic ductal adenocarcinoma (PDAC) Homologous recombination-DNA damage response defects Tumor mutation burden (TMB) T cell infiltration T cell clonal diversity Immune checkpoint inhibitors |
| title | Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer |
| title_full | Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer |
| title_fullStr | Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer |
| title_full_unstemmed | Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer |
| title_short | Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer |
| title_sort | homologous recombination dna damage response defects increase tmb and neoantigen load but not effector t cell density and clonal diversity in pancreatic cancer |
| topic | Pancreatic ductal adenocarcinoma (PDAC) Homologous recombination-DNA damage response defects Tumor mutation burden (TMB) T cell infiltration T cell clonal diversity Immune checkpoint inhibitors |
| url | https://doi.org/10.1186/s40164-025-00673-0 |
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