Pancreatic cancer is a highly aggressive cancer with a high mortality rate and limited treatment options. It is the fourth leading cause of cancer in the US, and mortality is rising rapidly, with a 12% relative 5-year survival rate. Early diagnosis remains a challenge due to vague symptoms, lack of specific biomarkers, and rapid tumor progression. Interleukin-12 (IL-12) is a central cytokine that regulates innate (natural killer cells) and adaptive (cytokine T-lymphocytes) immunity in cancer. We demonstrated that serum levels of IL-12p40 homodimer (p402) and p40 monomer (p40) were elevated and that of IL-12 and IL-23 were lowered in pancreatic cancer patients compared to healthy controls. Comparably, human PDAC cells produced greater levels of p402and p40 and lower levels of IL-12 and IL-23 compared to normal pancreatic cells. Notably, neutralization of p402by mAb a3-1d and p40 by mAb a3-3a induced the death of human PDAC cells, but not normal human pancreatic cells. Furthermore, we demonstrated that treatment of PDX mice with p402mAb and p40 mAb resulted in apoptosis and tumor shrinkage. This study illustrates a new role of p402and p40 monomer in pancreatic cancer, highlighting possible approaches against this deadly form of cancer with p402and p40 monomer immunotherapies.
胰腺癌是一种侵袭性极强的恶性肿瘤，死亡率高且治疗手段有限。在美国，该疾病位列癌症致死原因第四位，死亡率正快速上升，其五年相对生存率仅为12%。由于症状隐匿、缺乏特异性生物标志物以及肿瘤进展迅速，早期诊断仍面临巨大挑战。白细胞介素-12（IL-12）是调控癌症先天免疫（自然杀伤细胞）与适应性免疫（细胞毒性T淋巴细胞）的核心细胞因子。本研究发现，与健康对照组相比，胰腺癌患者血清中IL-12p40同源二聚体（p402）及p40单体水平显著升高，而IL-12与IL-23水平降低。相应地，人胰腺导管腺癌细胞较正常胰腺细胞产生更高水平的p402与p40，以及更低水平的IL-12与IL-23。值得注意的是，单克隆抗体a3-1d中和p402及单克隆抗体a3-3a中和p40可诱导人胰腺导管腺癌细胞死亡，但对正常人胰腺细胞无此效应。进一步研究显示，使用p402单抗与p40单抗治疗PDX小鼠可诱导细胞凋亡并缩小肿瘤体积。本研究揭示了p402同源二聚体与p40单体在胰腺癌中的新作用机制，为通过p402/p40单体免疫疗法治疗这种致命性癌症提供了潜在新策略。
肿瘤(癌症)患者之家