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

作者：Mengyue Lei, Jessica Gai, Thomas McPhaul, Huijuan Luo, Penghui Lin, Dongbing Liu, Michael J. Pishvaian, Nicholas J. Roberts, Kui Wu, Jing He, Lei Zheng · 发表于：Experimental Hematology and Oncology · 年份：2025 · DOI：10.1186/s40164-025-00673-0 · 被引用次数：7 · 研究领域：Pancreatic and Hepatic Oncology Research、Cancer Genomics and Diagnostics、Cancer Immunotherapy and Biomarkers

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 bur...