O'Neill Conor H, Tan Min, Yan Jun, Li Yan, Martin Robert C G
Division of Surgical Oncology, Price Surgical Research Institute, Hiram Polk Department of Surgery, University of Louisville Louisville, KY 40202, USA.
Division of Immunotherapy, Hiram Polk Department of Surgery, University of Louisville Louisville, KY 40202, USA.
Am J Cancer Res. 2022 Jan 15;12(1):165-175. eCollection 2022.
Comprehensive understanding of the immunophenotypic response to local therapy will likely be required to improve outcomes for pancreatic ductal adenocarcinoma (PDAC). While the desmoplastic stroma has rendered PDAC resistant to immunotherapies, irreversible electroporation (IRE), a non-thermal method of tumor ablation, can overcome some of this resistance and immune suppression. We studied the systemic immunophenotype of patients following local treatment of PDAC. Stored lymphocytes from peripheral blood collected pre- and post-operatively for patients with PDAC who underwent surgical treatment from 12/2018 until 12/2019 were prepared for mass cytometry and a 30-marker panel identifying 37 immune-cell clusters were analyzed and compared to all clinical parameters. Stored lymphocytes from patient samples were collected pre-operatively postoperatively (Day 1, 3, 5 and 14) and during surveillance (Month 3, 6, 9 and 12). Thirty patients with locally advanced pancreatic cancer (LAPC) who underwent IRE were evaluated prospectively for changes in their immunophenotype. No significant differences in baseline demographics or tumor markers were identified. CA19-9 levels were significantly higher among patients who developed a recurrence (P=0.03). In the early perioperative period, CD4 and CD8 central memory cells were significantly higher among patients who did not recur (P=0.02 and 0.009 respectively). These findings were maintained in the late (>3 month) surveillance period. Early natural killer (NK) cells were significantly higher among those who did not recur (P=0.004) in the early postoperative period. The early immune-cell populations of CD4 and CD8 central memory cells and early NK cells were significantly higher among populations who did not recur following IRE for PDAC during the study period, with maintenance of the CD4 and CD8 central memory populations during later surveillance. Monitoring the early immunophenotype may offer opportunities to augment the immune response following tumor-disruptive IRE for PDAC.
为改善胰腺导管腺癌（PDAC）的治疗效果，可能需要全面了解其对局部治疗的免疫表型反应。虽然促结缔组织增生性基质使PDAC对免疫疗法产生耐药性，但不可逆电穿孔（IRE）作为一种非热肿瘤消融方法，可以克服部分这种耐药性和免疫抑制。我们研究了PDAC局部治疗后患者的全身免疫表型。收集了2018年12月至2019年12月接受手术治疗的PDAC患者术前和术后外周血中储存的淋巴细胞，用于质谱流式细胞术分析，并使用一个识别37个免疫细胞簇的30标记物面板进行分析，并与所有临床参数进行比较。从患者样本中收集术前、术后（第1、3、5和14天）以及监测期间（第3、6、9和12个月）储存的淋巴细胞。对30例接受IRE治疗的局部晚期胰腺癌（LAPC）患者的免疫表型变化进行了前瞻性评估。未发现基线人口统计学或肿瘤标志物存在显著差异。复发患者的CA19-9水平显著更高（P=0.03）。在围手术期早期，未复发患者的CD4和CD8中央记忆细胞显著更高（分别为P=0.02和0.009）。这些发现在晚期（>3个月）监测期内得以维持。术后早期未复发患者的早期自然杀伤（NK）细胞显著更高（P=0.004）。在研究期间，接受PDAC的IRE治疗后未复发人群中，CD4和CD8中央记忆细胞以及早期NK细胞的早期免疫细胞群体显著更高，并且在后期监测中CD4和CD8中央记忆细胞群体得以维持。监测早期免疫表型可能为增强PDAC的肿瘤破坏性IRE后的免疫反应提供机会。
