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<p>Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. However, PDAC with germline <i>BRCA</i>&#xa0;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 <i>BRCA1, BRCA2, and PALB2</i>. 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 <i>RAD51B</i>, <i>BRCA2</i> and <i>ATM</i> 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.</p>

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Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月18日

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  • Mengyue Lei,
  • Jessica Gai,
  • Thomas J. McPhaul,
  • Huijuan Luo,
  • Penghui Lin,
  • Dongbing Liu,
  • Michael Pishvaian,
  • Nicholas J. Roberts,
  • Kui Wu,
  • Jin He,
  • Lei Zheng

摘要

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.