Napp Joanna, Siebel Paulina, Rausch Hans, Kuchta Kenny, Efferth Thomas, Alves Frauke, Ellenrieder Volker, Cameron Silke
Clinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen (UMG), Göttingen, Germany.
Translational Molecular Imaging, Max Planck Institute for Multidisciplinary Sciences (MPI-NAT), Göttingen, Germany.
Front Oncol. 2024 Dec 11;14:1454291. doi: 10.3389/fonc.2024.1454291. eCollection 2024.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. Traditional Japanese herbal medicine (Kampo), such as Juzentaihoto (a standardized combination of 10 herbal extracts), has shown immune modulatory effects, modulation of microcirculation, and amelioration of fatigue. It is administered to patients to prevent deterioration of cachexia and counteract side effects of chemotherapy. The effect of Juzentaihoto with or without standard chemotherapy (Gemcitabine) on survival and tumor microenvironment was studied in an immunocompetent pancreatic cancer mouse model. Following tumor development ±12 days after orthotopic implantation of murine pancreatic cancer cells (KPC) into the pancreas of C57BL/6 mice, the mice were treated with Gemcitabine, Juzentaihoto, their combination (Gem/Juz) or NaCl (Ctr.). Combination treatment significantly prolonged survival (+38%) of tumor bearing mice, compared to controls as well as Gemcitabine or Juzentaihoto monotherapy. Macrophage (CD68+) infiltration in pancreatic tumors was significantly enhanced in Gem/Juz - treated animals, compared with controls (p < 0,001), with significant increases of both, macrophages (CD68+) and for lymphocytes (CD45+), especially at the tumor front. , Juz- or Gem/Juz-treated KPC tumor cells secreted significantly more macrophage-chemoattractant cytokines, e.g., CCL2, CCL20, and CXCL2, whilst Juz- and Gem/Juz-treated macrophages (MH-S) secreted cytokines of the M1 phenotype, e.g., IL6, TNF-α, and IL12. It has been shown that tumor cells recruit and polarize macrophages towards tumor-associated macrophages (TAM). Our results indicate a change in macrophage polarization which not only induced anti-tumor immune-cell activity and cytokine release, but also suggests amelioration of Gemcitabine efficacy as DNA-analogue and as partial antitumor antigen. We propose that the increased survival of tumor bearing mice after Gem/Juz combination treatment is due to the restored cytotoxicity of Gemcitabine and changes in the tumor-microenvironment - induced by Juzentaihoto - such as an increased number of M1 macrophages.
胰腺导管腺癌（PDAC）的特点是预后较差。传统的日本草药（汉方），如十全大补汤（一种由10种草药提取物组成的标准化组合），已显示出免疫调节作用、微循环调节作用以及疲劳改善作用。它被用于患者以预防恶病质恶化并对抗化疗的副作用。在具有免疫活性的胰腺癌小鼠模型中研究了十全大补汤联合或不联合标准化化疗（吉西他滨）对生存和肿瘤微环境的影响。在将小鼠胰腺癌细胞（KPC）原位植入C57BL/6小鼠胰腺后约12天肿瘤发生发展后，小鼠接受吉西他滨、十全大补汤、它们的联合用药（吉西他滨/十全大补汤）或氯化钠（对照）治疗。与对照组以及吉西他滨或十全大补汤单药治疗相比，联合治疗显著延长了荷瘤小鼠的生存期（延长38%）。与对照组相比，吉西他滨/十全大补汤治疗的动物胰腺肿瘤中巨噬细胞（CD68+）浸润显著增强（p < 0.001），巨噬细胞（CD68+）和淋巴细胞（CD45+）均显著增加，尤其是在肿瘤前沿。十全大补汤或吉西他滨/十全大补汤治疗的KPC肿瘤细胞分泌显著更多的巨噬细胞趋化因子，如CCL2、CCL20和CXCL2，而十全大补汤和吉西他滨/十全大补汤治疗的巨噬细胞（MH-S）分泌M1表型的细胞因子，如IL6、TNF-α和IL12。已表明肿瘤细胞招募巨噬细胞并将其极化为肿瘤相关巨噬细胞（TAM）。我们的结果表明巨噬细胞极化发生了变化，这不仅诱导了抗肿瘤免疫细胞活性和细胞因子释放，还提示吉西他滨作为DNA类似物和部分抗肿瘤抗原的疗效得到改善。我们认为吉西他滨/十全大补汤联合治疗后荷瘤小鼠生存期延长是由于十全大补汤诱导的肿瘤微环境变化，如M1巨噬细胞数量增加，从而恢复了吉西他滨的细胞毒性。
