Sheinin Monica, Mondal Susanta, Pahan Kalipada
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
Cancers (Basel). 2023 Dec 11;15(24):5796. doi: 10.3390/cancers15245796.
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 (p40) 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 p40 and p40 and lower levels of IL-12 and IL-23 compared to normal pancreatic cells. Notably, neutralization of p40 by 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 p40 mAb and p40 mAb resulted in apoptosis and tumor shrinkage. This study illustrates a new role of p40 and p40 monomer in pancreatic cancer, highlighting possible approaches against this deadly form of cancer with p40 and p40 monomer immunotherapies.
胰腺癌是一种侵袭性很强的癌症，死亡率高且治疗选择有限。它是美国癌症的第四大主要病因，死亡率正在迅速上升，5年相对生存率为12%。由于症状模糊、缺乏特异性生物标志物以及肿瘤进展迅速，早期诊断仍然是一项挑战。白细胞介素-12（IL-12）是一种核心细胞因子，可调节癌症中的固有免疫（自然杀伤细胞）和适应性免疫（细胞因子T淋巴细胞）。我们证明，与健康对照相比，胰腺癌患者血清中IL-12p40同二聚体（p40）和p40单体（p40）水平升高，而IL-12和IL-23水平降低。同样，与正常胰腺细胞相比，人胰腺导管腺癌（PDAC）细胞产生更高水平的p40和p40，以及更低水平的IL-12和IL-23。值得注意的是，单克隆抗体a3-1d对p40和单克隆抗体a3-3a对p40的中和作用可诱导人PDAC细胞死亡，但不会诱导正常人类胰腺细胞死亡。此外，我们证明用p40单克隆抗体和p40单克隆抗体治疗PDX小鼠会导致细胞凋亡和肿瘤缩小。这项研究阐明了p40和p40单体在胰腺癌中的新作用，突出了通过p40和p40单体免疫疗法对抗这种致命癌症形式的可能方法。
