Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human tumors, with radical surgical resection as the only curative treatment option. However, resection is only possible in a small fraction of patients, and about 80% of the patients develop recurrencies. PDAC development is facilitated by the cytokine interleukin-6 (IL-6), which acts via classic and trans-signaling. Both pathways are inhibited by the anti-IL-6-receptor antibody tocilizumab, whereas the fusion protein sgp130Fc specifically blocks trans-signaling. Here, we show that conservative or adjuvant therapy with both inhibitors reduces tumor growth in an orthotopic model of human Colo357 cells in SCID/bg mice. In the conservative setting, median primary tumor weight was reduced 2.4-fold for tocilizumab and 4.4-fold for sgp130Fc. sgp130Fc additionally led to a decrease in microvessel density, which was not observed with tocilizumab. In the adjuvant therapeutic setting after surgical resection of the primary tumor, treatment with tocilizumab or sgp130Fc decreased the local recurrence rate from 87.5% in the control group to 62.5 or 50%, respectively. Furthermore, the median weight of the local recurrent tumors was clearly diminished, and both inhibitors reduced the number of distant metastases. A significant reduction of tumor weight and metastasescomparable to gemcitabine treatmentwas also observed with both inhibitors in another model using the poorly differentiated PancTuI cells. Our findings demonstrate the inhibition of IL-6 as a new treatment option in PDAC. What's new? IL-6 plays a critical role in the progression of pancreatic cancer, and its inhibition may be key in the therapeutic battle against the disease. IL-6 acts through both an anti-inflammatory classic signaling pathway involving membrane-bound IL-6R and a pro-inflammatory trans-signaling pathway involving soluble IL-6R and gp130. Using a clinically adapted xenotransplant model, this study shows that inhibition of both pathways, with either tocilizumab or sgp130Fc, which specifically blocks trans-signaling, leads to significant reductions in human pancreatic tumor growth. Following surgical resection of primary tumors, the inhibitors decreased local tumor recurrence rates and reduced numbers of distant metastases.