Neutralization of p40 Homodimer and p40 Monomer Leads to Tumor Regression in Patient-Derived Xenograft Mice with Pancreatic Cancer

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and immunotherapy could be one of the safest options to control PDAC. Although the p40 family of cytokines has four members comprising IL-12, p40 homodimer (p402), p40 monomer (p40), and IL-23, we found an increase in p402 and p40 and a decrease in IL-12 and IL-23 in serum of pancreatic cancer patients as compared to healthy controls. Similarly, human pancreatic cancer cells also produced greater levels of p402 and p40 and lower levels of IL-12 and IL-23 than normal human pancreatic cells. Accordingly, neutralization of p402 by a3-1d monoclonal antibody (mAb) and p40 by a3-3a mAb separately led to apoptosis of pancreatic cancer cells and tumor shrinkage in a patient-derived xenograft (PDX) mouse model of pancreatic cancer, highlighting the possible therapeutic potential of mAbs against p402 and p40 in pancreatic cancer.Abstract 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 p402 and p40 and lower levels of IL-12 and IL-23 compared to normal pancreatic cells. Notably, neutralization of p402 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 p402 mAb and p40 mAb resulted in apoptosis and tumor shrinkage. This study illustrates a new role of p402 and p40 monomer in pancreatic cancer, highlighting possible approaches against this deadly form of cancer with p402 and p40 monomer immunotherapies.