尽管免疫检查点抑制剂（ICIs）取得了进展，化疗仍然是胰腺导管腺癌（PDAC）患者的标准治疗方法。由于化疗组合，包括 FOLFIRINOX（5-氟尿嘧啶 (5FU)、伊立替康和奥沙利铂）方案和 ICI 未能证明对转移性 PDAC 肿瘤患者有临床益处，因此人们越来越有兴趣确定增强 ICI 的治疗方法PDAC 患者的疗效。在这项研究中，我们报告新辅助 FOLFRINOX 治疗的人 PDAC 肿瘤表现出 MEK/ERK 激活增加。我们还显示，在用 5FU (F)、伊立替康 (I) 和奥沙利铂 (O) (FIO) 组合处理的离体 PDAC 切片培养物和细胞系中，MEK/ERK 信号传导增强。此外，我们发现，通过用 FIO 重复处理小鼠 PDAC 细胞系 6-8 个周期而建立的 KPC-FIO 细胞显示出增强的 ERK 磷酸化，并且在体外和体内表现出对 MEK 抑制的敏感性增加。值得注意的是，新辅助 FOLFIRINOX 治疗后，KPC-FIO 细胞形成的肿瘤具有与人 PDAC 肿瘤相似的促炎免疫特征。此外，我们发现 MEK 抑制剂 Trametinib 能够使高功能 CD8 T 细胞额外浸润到 KPC-FIO 肿瘤中，并增强抗 PD-1 抗体在同基因小鼠模型中的功效。我们的研究结果为 PDAC 患者在新辅助或短期 FOLFIRINOX 治疗后联合使用 Trametinib 和抗 PD-1 抗体以实现有效的抗肿瘤反应提供了理论基础。

Despite advances in immune checkpoint inhibitors (ICIs), chemotherapy remains the standard therapy for patients with pancreatic ductal adenocarcinoma (PDAC). As the combinations of chemotherapy, including the FOLFIRINOX (5-fluorouracil (5FU), irinotecan, and oxaliplatin) regimen, and ICIs have failed to demonstrate clinical benefit in patients with metastatic PDAC tumors, there is increasing interest in identifying therapeutic approaches to potentiate ICI efficacy in PDAC patients. In this study, we report that neoadjuvant FOLFRINOX-treated human PDAC tumors exhibit increased MEK/ERK activation. We also show elevated MEK/ERK signaling in ex vivo PDAC slice cultures and cell lines treated with a combination of 5FU (F), irinotecan (I), and oxaliplatin (O) (FIO). In addition, we find that the KPC-FIO cells, established from repeated treatment of mouse PDAC cell lines with 6-8 cycles of FIO, display enhanced ERK phosphorylation and demonstrate increased sensitivity to MEK inhibition in vitro and in vivo. Significantly, the KPC-FIO cells develop tumors with a pro-inflammatory immune profile similar to human PDAC tumors following neoadjuvant FOLFIRINOX treatment. Furthermore, we found that the MEK inhibitor Trametinib enables additional infiltration of highly functional CD8+ T cells into the KPC-FIO tumors and potentiates the efficacy of anti-PD-1 antibody in syngeneic mouse models. Our findings provide a rationale for combining Trametinib and anti-PD-1 antibodies in PDAC patients following neoadjuvant or short-term FOLFIRINOX treatment to achieve effective anti-tumor responses.